Gene Detail

Gene Symbol SMAD4
Synonyms DPC4 | JIP | MADH4 | MYHRS
Gene Description SMAD4, mothers against decapentaplegic homolog 4, is a tumor suppressor (PMID: 30562755) that translocates to the nucleus upon TGF-beta signaling to form a protein complex that regulates gene transcription and cell growth (PMID: 28452926). SMAD4 germline mutations are associated with juvenile polyposis syndrome (PMID: 18559331) and Smad4 loss of function or inactivation is common in prostate, colorectal (PMID: 29720405), and pancreatic cancer, which may be a marker for poor prognosis (PMID: 28067794).
ACMG Incidental List v2.0:
Yes, Juvenile polyposis syndrome, (PMID: 27854360)
Entrez Id 4089
Chromosome 18
Map Location 18q21.2
Canonical Transcript NM_005359

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
H132Tfs*15 frameshift loss of function - predicted SMAD4 H132Tfs*15 indicates a shift in the reading frame starting at amino acid 132 and terminating 15 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). H132Tfs*15 has not been characterized however, due to the effects of other truncation mutations downstream of H132 (PMID: 11553622, PMID: 22316667), H132Tfs*15 is predicted to lead to a loss of Smad4 protein function.
P102L missense loss of function SMAD4 P102L lies in the MH1 domain of the Smad4 protein (UniProt.org). P102L confers a loss of function to the Smad4 protein as demonstrated by reduced transactivating activity and loss of DNA binding in cell assays (PMID: 14647410).
L57V missense unknown SMAD4 L57V lies within the MH1 domain of the Smad4 protein (UniProt.org). L57V has been identified in sequencing studies (PMID: 25855536), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E330K missense unknown SMAD4 E330K lies within the MH2 domain of the Smad4 protein (UniProt.org). E330K has been identified in sequencing studies (PMID: 28027327, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
I383R missense unknown SMAD4 I383R lies within the MH2 domain of the Smad4 protein (UniProt.org). I383R has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
P246R missense unknown SMAD4 P246R does not lie within any known functional domains of the Smad4 protein (UniProt.org). P246R has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
F505Y missense unknown SMAD4 F505Y lies within the MH2 domain of the Smad4 protein (UniProt.org). F505Y has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G419W missense unknown SMAD4 G419W lies within the MH2 domain of the Smad4 protein (UniProt.org). G419W has been identified in the scientific literature (PMID: 23139211, PMID: 28796828), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
K507A missense loss of function SMAD4 K507A lies in the MH2 domain of the Smad4 protein (UniProt.org). K507A confers a loss of function to the Smad4 protein as demonstrated by the inability to interact with Smad2, impaired TGF beta signaling, and reduced transactivating activity in cell assays (PMID: 12794086).
E330G missense no effect - predicted SMAD4 E330G lies within the MH2 domain of the Smad4 protein (UniProt.org). E330G results in a slight reduction in BMP signaling in cell culture, but is not significantly different from wild-type Smad4 (PMID: 22316667) and therefore, is predicted to have no effect on Smad4 protein function.
D537H missense no effect - predicted SMAD4 D537H lies within the MH2 domain of the Smad4 protein (UniProt.org). D537H is predicted to have no effect on Smad4 protein function as demonstrated by unaltered heterodimerization of purified Smad4 and Smad2 proteins (PMID: 11274206).
S144* nonsense loss of function - predicted SMAD4 S144* results in a premature truncation of the Smad4 protein at amino acid 144 of 552 (UniProt.org). S144* has not been characterized however, due to the effects of other truncation mutations downstream of S144 (PMID: 11553622, PMID: 22316667), S144* is predicted to lead to a loss of Smad4 protein function.
A226T missense no effect - predicted SMAD4 A226T lies within the linker region of the Smad4 protein (PMID: 22109972). A226T does not result in increased transcriptional activation as compared to wild-type Smad4 in cell culture (PMID: 22109972) and therefore, is predicted to have no effect on Smad4 protein function.
D351Y missense unknown SMAD4 D351Y lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org, PMID: 23139211). D351Y has been identified in sequencing studies (PMID: 28481359, PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
inact mut unknown loss of function SMAD4 inact mut indicates that this variant results in a loss of function of the Smad4 protein. However, the specific amino acid change has not been identified.
G510E missense unknown SMAD4 G510E lies within the MH2 domain of the Smad4 protein (UniProt.org). G510E has been identified in sequencing studies (PMID: 27149842, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R420C missense unknown SMAD4 R420C lies within the MH2 domain of the Smad4 protein (UniProt.org). R420C has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
K436N missense no effect - predicted SMAD4 K436N lies in the MH2 domain of the Smad4 protein (UniProt.org). K436N has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smad4 (PMID: 29533785).
V44G missense unknown SMAD4 V44G lies within the MH1 domain of the Smad4 protein (UniProt.org). V44G has been identified in sequencing studies (PMID: 23103869), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
dec exp none no effect SMAD4 dec exp indicates decreased expression of the Smad4 protein. However, the mechanism causing the decreased expression is unspecified.
G65V missense loss of function - predicted SMAD4 G65V lies within the MH1 domain of the Smad4 protein (UniProt.org). G65V is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced protein stability as compared to wild-type (PMID: 12794086).
W524C missense unknown SMAD4 W524C lies in the MH2 domain of the Smad4 protein (UniProt.org). W524C demonstrates expression and nuclear localization (PMID: 26020105), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
H382L missense unknown SMAD4 H382L lies within the MH2 domain of the Smad4 protein (UniProt.org). H382L has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
Q448fs frameshift loss of function - predicted SMAD4 Q448fs results in a change in the amino acid sequence of the Smad4 protein beginning at 448 of 552, likely resulting in premature truncation of the functional protein (UniProt.org). Q448fs is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
E526K missense unknown SMAD4 E526K lies within the MH2 domain of the Smad4 protein (UniProt.org). E526K has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
G386V missense unknown SMAD4 G386V lies within the MH2 domain of the Smad4 protein (UniProt.org). G386V has been identified in sequencing studies (PMID: 22895193, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
Q249H missense unknown SMAD4 Q249H does not lie within any known functional domains of the Smad4 protein (UniProt.org). Q249H has been identified in sequencing studies (PMID: 25623214), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D415Efs*20 frameshift loss of function - predicted SMAD4 D415Efs*20 indicates a shift in the reading frame starting at amino acid 415 and terminating 20 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). D415Efs*20 is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
W99C missense unknown SMAD4 W99C lies within the MH1 domain of the Smad4 protein (UniProt.org). W99C has been identified in sequencing studies (PMID: 26046389), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
A452T missense unknown SMAD4 A452T lies within the MH2 domain of the Smad4 protein (UniProt.org). A452T has been identified in the scientific literature (PMID: 23139211, PMID: 28199989), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
D355G missense unknown SMAD4 D355G lies within the MH2 domain of the Smad4 protein (UniProt.org). D355G has been identified in sequencing studies (PMID: 29420467, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E526* nonsense loss of function - predicted SMAD4 E526* results in a premature truncation of the Smad4 protein at amino acid 526 of 552 (UniProt.org). E526* has not been characterized however, due to the effects of other truncation mutants downstream of E526 (PMID: 22316667), E526* is predicted to lead to a loss of Smad4 protein function.
D493N missense unknown SMAD4 D493N lies within the MH2 domain of the Smad4 protein (UniProt.org). D493N has been identified in sequencing studies (PMID: 27287813, PMID: 24997986), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G65R missense unknown SMAD4 G65R lies within the MH1 domain of the Smad4 protein (UniProt.org). G65R has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
R380K missense unknown SMAD4 R380K lies within the MH2 domain of the Smad4 protein (UniProt.org). R380K has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L98F missense unknown SMAD4 L98F lies within the MH1 domain of the Smad4 protein (UniProt.org). L98F is predicted to result in decreased Smad4 protein stability in computational models (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A460S missense unknown SMAD4 A460S lies within the MH2 domain of the Smad4 protein (UniProt.org). A460S has been identified in the scientific literature (PMID: 23139211, PMID: 29451897), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
L43S missense loss of function SMAD4 L43S lies in the MH1 domain of the Smad4 protein (UniProt.org). L43S confers a loss of function to the Smad4 protein as demonstrated by reduced stability and increased poly-ubiquitination and proteasomal degradation, as compared to wild-type (PMID: 12794086).
P130Q missense unknown SMAD4 P130Q lies in the MH1 domain of the Smad4 protein (UniProt.org). P130Q has not been characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R515T missense unknown SMAD4 R515T lies within the MH2 domain of the Smad4 protein (UniProt.org). R515T has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
E167fs frameshift loss of function - predicted SMAD4 E167fs results in a change in the amino acid sequence of the Smad4 protein beginning at aa 167 of 552, likely resulting in premature truncation of the functional protein (UniProt.org). E167fs has not been characterized, however, due to the effects of other truncation mutations downstream of E167 (PMID: 11553622, PMID: 22316667), E167fs is predicted to lead to a loss of Smad4 protein function.
G419R missense unknown SMAD4 G419R lies within the MH2 domain of the Smad4 protein (UniProt.org). G419R has been identified in the scientific literature (PMID: 23139211, PMID: 25938944), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
K519N missense unknown SMAD4 K519N lies within the MH2 domain of the Smad4 protein (UniProt.org). K519N has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D537Y missense loss of function SMAD4 D537Y lies within the MH2 domain of the Smad4 protein (UniProt.org). D537Y results in a loss of Smad4 protein function as indicated by failure to form a functional transcriptional complex with activated Smad2 and Smad3, and absence of nuclear translocation after TGF-beta stimulation in cell culture (PMID: 14715079).
wild-type none no effect Wild-type SMAD4 indicates that no mutation has been detected within the SMAD4 gene.
P91S missense unknown SMAD4 P91S lies within the MH1 domain of the Smad4 protein (UniProt.org). P91S has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A60P missense unknown SMAD4 A60P lies within the MH1 domain of the Smad4 protein (UniProt.org). A60P has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R135* nonsense loss of function - predicted SMAD4 R135* results in a premature truncation of the Smad4 protein at amino acid 135 of 552 (UniProt.org). R135* has not been characterized however, due to the effects of other truncation mutations downstream of R135 (PMID: 11553622, PMID: 22316667), R135* is predicted to lead to a loss of Smad4 protein function.
R361S missense no effect - predicted SMAD4 R361S lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). R361S results in a slight reduction in BMP signaling in cell culture, but is not significantly different from wild-type Smad4 (PMID: 22316667) and therefore, is predicted to have no effect on Smad4 protein function.
H132Y missense loss of function - predicted SMAD4 H132Y lies within the MH1 domain of the Smad4 protein (UniProt.org). H132Y is predicted to confer a loss of function to the Smad4 protein as indicated by failure to phosphorylate receptor-activated Smads after TGF-beta stimulation in cell culture (PMID: 25275298).
K507R missense loss of function SMAD4 K507R lies in the MH2 domain of the Smad4 protein (UniProt.org). K507R confers a loss of function to the Smad4 protein as demonstrated by the inability to interact with Smad2, impaired TGF beta signaling, and reduced transactivating activity in cell assays (PMID: 12794086).
E526A missense unknown SMAD4 E526A lies within the MH2 domain of the Smad4 protein (UniProt.org). E526A has been identified in sequencing studies (PMID: 24816253), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L367P missense unknown SMAD4 L367P lies within the MH2 domain of the Smad4 protein (UniProt.org). L367P has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A457S missense unknown SMAD4 A457S lies within the MH2 domain of the Smad4 protein (UniProt.org). A457S has been identified in sequencing studies (PMID: 10327057), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
K340N missense unknown SMAD4 K340N lies within the MH2 domain of the Smad4 protein (UniProt.org). K340N has been identified in sequencing studies (PMID: 24755471, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L43V missense loss of function SMAD4 L43V lies in the MH1 domain of the Smad4 protein (UniProt.org). L43V confers a loss of function to the Smad4 protein as demonstrated by reduced transactivating activity and loss of DNA binding in cell assays (PMID: 14647410).
W524R missense unknown SMAD4 W524R lies within the MH2 domain of the Smad4 protein (UniProt.org). W524R has been identified in sequencing studies (PMID: 27432539), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
G299R missense unknown SMAD4 G299R does not lie within any known functional domains of the Smad4 protein (UniProt.org). G299R has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
C324Y missense gain of function SMAD4 C324Y lies within the MH2 domain of the Smad4 protein (UniProt.org). C324Y confers a gain of function to the Smad4 protein as demonstrated by increased transcriptional activity, increased interaction with Smad2, and induction of cell proliferation (PMID: 22109972, PMID: 23591542).
D355V missense unknown SMAD4 D355V lies within the MH2 domain of the Smad4 protein (UniProt.org). D355V has been identified in sequencing studies (PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L495P missense unknown SMAD4 L495P lies within the MH2 domain of the Smad4 protein (UniProt.org). L495P has been identified in sequencing studies (PMID: 22014273), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G510V missense unknown SMAD4 G510V lies within the MH2 domain of the Smad4 protein (UniProt.org). G510V has been identified in the scientific literature (PMID: 23139211, PMID: 25695693, PMID: 27459628), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
Y133N missense unknown SMAD4 Y133N lies within the MH1 domain of the Smad4 protein (UniProt.org). Y133N has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
A406T missense loss of function - predicted SMAD4 A406T lies within the MH2 domain of the Smad4 protein (UniProt.org). A406T is analogous to A354T in SMAD2 and is predicted to impair Smad4 oligomerization and transcriptional activity of the Smad complex (PMID: 23139211).
D355N missense unknown SMAD4 D355N lies within the MH2 domain of the Smad4 protein (UniProt.org). D355N has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
W509G missense unknown SMAD4 W509G lies within the MH2 domain of the Smad4 protein (UniProt.org). W509G has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
S178* nonsense loss of function - predicted SMAD4 S178* results in a premature truncation of the Smad4 protein at amino acid 178 of 552 (UniProt.org). S178* has not been characterized however, due to the effects of other truncation mutations downstream of S178 (PMID: 11553622, PMID: 22316667), S178* is predicted to lead to a loss of Smad4 protein function.
Q245* nonsense loss of function - predicted SMAD4 Q245* results in a premature truncation of the Smad4 protein at amino acid 245 of 552 (UniProt.org). Q245* has not been characterized however, due to the effects of other truncation mutations downstream of Q245 (PMID: 11553622, PMID: 22316667), Q245* is predicted to lead to a loss of Smad4 protein function.
E538K missense unknown SMAD4 E538K lies within the MH2 domain of the Smad4 protein (UniProt.org). E538K has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R361H missense unknown SMAD4 R361H lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). R361H is predicted to result in a loss of heterocomplex formation (PMID: 21763698), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E161K missense unknown SMAD4 E161K does not lie within any known functional domains of the Smad4 protein (UniProt.org). E161K has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
P130S missense loss of function SMAD4 P130S lies within the MH1 domain of the Smad4 protein (UniProt.org). P130S confers a loss of function to the Smad4 protein as demonstrated by reduced transactivating activity and DNA binding in cell assays (PMID: 14647410) and also has decreased stability as compared to wild-type (PMID: 12794086).
G352V missense unknown SMAD4 G352V lies within the MH2 domain of the Smad4 protein (UniProt.org). G352V has been identified in the scientific literature (PMID: 23139211, PMID: 26919633), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
C499R missense unknown SMAD4 C499R lies within the MH2 domain of the Smad4 protein (UniProt.org). C499R has been identified in the scientific literature (PMID: 23139211, PMID: 29117359, PMID: 26475379), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
R531Q missense unknown SMAD4 R531Q lies within the MH2 domain of the Smad4 protein (UniProt.org). R531Q has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
G231Afs*10 frameshift loss of function - predicted SMAD4 G231Afs*10 indicates a shift in the reading frame starting at amino acid 231 and terminating 10 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). G231Afs*10 has not been characterized however, due to the effects of other truncation mutations downstream of G231 (PMID: 11553622, PMID: 22316667), G231Afs*10 is predicted to lead to a loss of Smad4 protein function.
P356L missense unknown SMAD4 P356L lies within the MH2 domain of the Smad4 protein (UniProt.org). P356L has been identified in sequencing studies (PMID: 23139211, PMID: 14647445), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E538* nonsense unknown SMAD4 E538* results in a premature truncation of the Smad4 protein at amino acid 538 of 552 (UniProt.org). E538* has been identified in sequencing studies (PMID: 23139211, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G386D missense loss of function - predicted SMAD4 G386D lies in the MH2 domain of the Smad4 protein (UniProt.org). G386D was identified as the underlying genetic defect for a case of juvenile polyposis and hereditary hemorrhagic telangiectasia (PMID: 12116240, PMID: 15031030), likely due to loss of function, and also displayed decreased transcriptional activity on Smad4 (PMID: 20101697, PMID: 26488212).
D494Y missense unknown SMAD4 D494Y lies within the MH2 domain of the Smad4 protein (UniProt.org). D494Y has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
R515G missense loss of function SMAD4 R515G lies in the MH2 domain of the Smad4 protein (UniProt.org). R515G confers a loss of function to the Smad4 protein as demonstrated by the inability to interact with Smad2 and displays reduced transactivating activity and DNA binding in cell assays (PMID: 14647410).
Y133H missense unknown SMAD4 Y133H lies within the MH1 domain of the Smad4 protein (UniProt.org). Y133H has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
R445* nonsense loss of function - predicted SMAD4 R445* results in a premature truncation of the Smad4 protein at amino acid 445 of 552 (UniProt.org). R445* has not been characterized however, due to the effects of other truncation mutations downstream of R445 (PMID: 11553622, PMID: 22316667), R445* is predicted to lead to a loss of Smad4 protein function.
del deletion loss of function SMAD4 del indicates a deletion of the SMAD4 gene.
S343* nonsense loss of function - predicted SMAD4 S343* results in a premature truncation of the Smad4 protein at amino acid 343 of 552 (UniProt.org). S343* has not been characterized however, due to the effects of other truncation mutations downstream of S343 (PMID: 11553622, PMID: 22316667), S343* is predicted to lead to a loss of Smad4 protein function.
W509R missense no effect - predicted SMAD4 W509R lies within the MH2 domain of the Smad4 protein (UniProt.org). W509R results in a slight reduction in BMP signaling in cell culture, but is not significantly different from wild-type Smad4 (PMID: 22316667) and therefore, is predicted to have no effect on Smad4 protein function.
L536Qfs*16 frameshift unknown SMAD4 L536Qfs*16 indicates a shift in the reading frame starting at amino acid 536 and terminating 16 residues downstream, resulting in premature truncation of the functional 552 aa Smad4 protein (UniProt.org). L536Qfs*16 has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
L104F missense unknown SMAD4 L104F lies within the MH1 domain of the Smad4 protein (UniProt.org). L104F has been identified in sequencing studies (PMID: 22810696, PMID: 26343386), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E417Sfs*11 frameshift loss of function - predicted SMAD4 E417Sfs*11 indicates a shift in the reading frame starting at amino acid 417 and terminating 11 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). E417Sfs*11 has not been characterized however, due to the effects of other truncation mutations downstream of E417 (PMID: 11553622, PMID: 22316667), E417Sfs*11 is predicted to lead to a loss of Smad4 protein function.
Q388* nonsense loss of function - predicted SMAD4 Q388* results in a premature truncation of the Smad4 protein at amino acid 388 of 552 (UniProt.org). Q388* is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
L536P missense unknown SMAD4 L536P lies within the MH2 domain of the Smad4 protein (UniProt.org). L536P has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
K507Q missense loss of function SMAD4 K507Q lies in the MH2 domain of the Smad4 protein (UniProt.org). K507Q confers a loss of function on the Smad4 protein as demonstrated by the inability to interact with Smad2 and reduced transactivating activity and DNA binding in cell assays (PMID: 14647410).
R100W missense unknown SMAD4 R100W lies within the MH1 domain of the Smad4 protein (UniProt.org). R100W has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R496H missense loss of function - predicted SMAD4 R496H lies within the MH2 domain of the Smad4 protein (UniProt.org). R496H is predicted to confer a loss of function to the Smad4 protein as demonstrated by decreased transcriptional activity in a reporter assay (PMID: 26488212).
L536Q missense unknown SMAD4 L536Q lies within the MH2 domain of the Smad4 protein (UniProt.org). L536Q has been identified in sequencing studies (PMID: 23103869), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D493A missense loss of function - predicted SMAD4 D493A lies within the MH2 domain of the Smad4 protein (UniProt.org). D493A is predicted to confer a loss of function to the Smad4 protein as demonstrated by decreased binding to receptor-activated Smads in cell culture (PMID: 15350224).
L540H missense unknown SMAD4 L540H lies within the MH2 domain of the Smad4 protein (UniProt.org). L540H has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L540R missense loss of function - predicted SMAD4 L540R lies within the MH2 domain of the Smad4 protein (UniProt.org). L540R is predicted to confer a loss of function to the Smad4 protein as demonstrated by impaired oligomerization (PMID: 11481457).
E337K missense unknown SMAD4 E337K lies within the MH2 domain of the Smad4 protein (UniProt.org). E337K has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
K428T missense unknown SMAD4 K428T lies within the MH2 domain of the Smad4 protein (UniProt.org). K428T has been identified in sequencing studies (PMID: 23139211, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R361P missense unknown SMAD4 R361P lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). R361P has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A433T missense unknown SMAD4 A433T lies within the MH2 domain of the Smad4 protein (UniProt.org). A433T has been identified in sequencing studies (PMID: 9515793), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A532V missense unknown SMAD4 A532V lies within the MH2 domain of the Smad4 protein (UniProt.org). A532V has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
P356delinsQK indel unknown SMAD4 P356delinsQK results in a deletion of proline (P) at amino acid 356 within the MH2 domain of the Smad4 protein, combined with the insertion of a glutamine (Q) and a lysine (K) at the same site (UniProt.org). P356delinsQK has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
V437D missense unknown SMAD4 V437D lies within the MH2 domain of the Smad4 protein (UniProt.org). V437D has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
E526V missense unknown SMAD4 E526V lies within the MH2 domain of the Smad4 protein (UniProt.org). E526V has been identified in sequencing studies (PMID: 23103869), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L172M missense unknown SMAD4 L172M does not lie within any known functional domain of the Smad4 protein (UniProt.org). L172M has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
L533R missense unknown SMAD4 L533R lies within the MH2 domain of the Smad4 protein (UniProt.org). L533R has been identified in sequencing studies (PMID: 23700467), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
W524S missense unknown SMAD4 W524S lies within the MH2 domain of the Smad4 protein (UniProt.org). W524S has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
C363Y missense unknown SMAD4 C363Y lies within the MH2 domain of the Smad4 protein (UniProt.org). C363Y has been identified in sequencing studies (PMID: 29360550, PMID: 24755471), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
H382D missense unknown SMAD4 H382D lies within the MH2 domain of the Smad4 protein (UniProt.org). H382D has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
P356S missense unknown SMAD4 P356S lies within the MH2 domain of the Smad4 protein (UniProt.org). P356S has been identified in sequencing studies (PMID: 25343854, PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R97H missense unknown SMAD4 R97H lies within the MH1 domain of the Smad4 protein (UniProt.org). R97H has been identified in sequencing studies (PMID: 25042771, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
Y353N missense unknown SMAD4 Y353N lies within the MH2 domain of the Smad4 protein (UniProt.org). Y353N has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
R76K missense unknown SMAD4 R76K lies within the MH1 domain of the Smad4 protein (UniProt.org). R76K has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
R100T missense loss of function SMAD4 R100T lies in the MH1 domain of the Smad4 protein (UniProt.org). R100T displays reduced Smad4 transactivating activity and loss of DNA binding in cell assays (PMID: 14647410) and has greatly reduced protein stability as compared to wild-type (PMID: 12794086).
V465M missense no effect - predicted SMAD4 V465M lies within the MH2 domain of the Smad4 protein (UniProt.org). V465M results in a slight reduction in BMP signaling in cell culture, but is not significantly different from wild-type Smad4 (PMID: 22316667) and therefore, is predicted to have no effect on Smad4 protein function.
R189C missense unknown SMAD4 R189C does not lie within any known functional domains of the Smad4 protein (UniProt.org). R189C has been identified in sequencing studies (PMID: 25186949, PMID: 27756406), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
W398* nonsense loss of function - predicted SMAD4 W398* results in a premature truncation of the Smad4 protein at amino acid 398 of 552 (UniProt.org). W398* is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
Q83* nonsense loss of function - predicted SMAD4 Q83* results in a premature truncation of the Smad4 protein at amino acid 83 of 552 (UniProt.org). Q83* has not been characterized however, due to the effects of other truncation mutations downstream of Q83 (PMID: 11553622, PMID: 22316667), Q83* is predicted to lead to a loss of Smad4 protein function.
L109Q missense unknown SMAD4 L109Q lies within the MH1 domain of the Smad4 protein (UniProt.org). L109Q has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
L109R missense unknown SMAD4 L109R lies within the MH1 domain of the Smad4 protein (UniProt.org). L109R has been identified in sequencing studies (PMID: 27245685), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A451Lfs*17 frameshift loss of function - predicted SMAD4 A451Lfs*17 indicates a shift in the reading frame starting at amino acid 451 and terminating 17 residues downstream, resulting in premature truncation of the 552 aa Smad4 protein (UniProt.org). A451Lfs*17 has not been characterized however, due to the effects of other truncation mutations downstream of A451 (PMID: 11553622, PMID: 22316667), A451Lfs*17 is predicted to lead to a loss of Smad4 protein function.
W509* nonsense loss of function - predicted SMAD4 W509* results in a premature truncation of the Smad4 protein at amino acid 509 of 552 (UniProt.org). W509* has not been characterized however, due to the effects of other truncation mutations downstream of W509 (PMID: 11553622, PMID: 22316667), W509* is predicted to lead to a loss of Smad4 protein function.
E134K missense unknown SMAD4 E134K lies within the MH1 domain of the Smad4 protein (UniProt.org). E134K has been identified in sequencing studies (PMID: 28042953, PMID: 28243320), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
H92Y missense unknown SMAD4 H92Y lies within the MH1 domain of the Smad4 protein (UniProt.org). H92Y has been identified in sequencing studies (PMID: 29642553), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
P203Hfs*38 frameshift loss of function - predicted SMAD4 P203Hfs*38 indicates a shift in the reading frame starting at amino acid 203 and terminating 38 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). P203Hfs*38 is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
G352A missense unknown SMAD4 G352A lies within the MH2 domain of the Smad4 protein (UniProt.org). G352A has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G80R missense unknown SMAD4 G80R lies within the MH1 domain of the Smad4 protein (UniProt.org). G80R has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G386C missense unknown SMAD4 G386C lies within the MH2 domain of the Smad4 protein (UniProt.org). G386C has been identified in sequencing studies (PMID: 10451707), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A118V missense unknown SMAD4 A118V lies within the MH1 domain of the Smad4 protein (UniProt.org). A118V has been identified in sequencing studies (PMID: 29420467, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G252* nonsense loss of function SMAD4 G252* results in a premature truncation of the Smad4 protein at amino acid 252 of 552 (UniProt.org). G252*confers a loss of function on Smad4 as demonstrated by decreased transcriptional activity and increased cell proliferation (PMID: 26488212).
G510R missense unknown SMAD4 G510R lies within the MH2 domain of the Smad4 protein (UniProt.org). G510R has been identified in sequencing studies (PMID: 27194209, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
mutant unknown unknown SMAD4 mutant indicates an unspecified mutation in the SMAD4 gene.
P470H missense unknown SMAD4 P470H lies within the MH2 domain of the Smad4 protein (UniProt.org). P470H has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G419V missense loss of function - predicted SMAD4 G419V lies within the MH2 domain of the Smad4 protein (UniProt.org). G419V is predicted to confer a loss of function to the Smad4 protein as demonstrated by decreased transcriptional activity in a reporter assay (PMID: 26488212).
G510Dfs*27 frameshift loss of function - predicted SMAD4 G510Dfs*27 indicates a shift in the reading frame starting at amino acid 510 and terminating 27 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). G510Dfs*27 has not been characterized however, due to the effects of other truncation mutations downstream of G510 (PMID: 11553622, PMID: 22316667), G510Dfs*27 is predicted to lead to a loss of Smad4 protein function.
H541Y missense unknown SMAD4 H541Y lies within the MH2 domain of the Smad4 protein (UniProt.org). H541Y has been identified in sequencing studies (PMID: 22610119, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
loss unknown loss of function SMAD4 loss indicates the loss of the SMAD4 gene, mRNA or protein.
D351N missense unknown SMAD4 D351N lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org, PMID: 23139211). D351N has been identified in sequencing studies (PMID: 28481359, PMID: 16959974), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
Y353H missense unknown SMAD4 Y353H lies within the MH2 domain of the Smad4 protein (UniProt.org). Y353H has been identified in the scientific literature (PMID: 23139211, PMID: 30730996), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
A327V missense unknown SMAD4 A327V lies within the MH2 domain of the Smad4 protein (UniProt.org). A327V has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
S368C missense unknown SMAD4 S368C lies within the MH2 domain of the Smad4 protein (UniProt.org). S368C has been identified in sequencing studies (PMID: 25617745), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
S504R missense unknown SMAD4 S504R lies within the MH2 domain of the Smad4 protein (UniProt.org). S504R has been identified in sequencing studies (PMID: 10451707, PMID: 25846456), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
D351A missense unknown SMAD4 D351A lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org, PMID: 23139211). D351A has been identified in sequencing studies (PMID: 26489445), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D537V missense unknown SMAD4 D537V lies within the MH2 domain of the Smad4 protein (UniProt.org). D537V has been identified in sequencing studies (PMID: 27149842, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G352R missense unknown SMAD4 G352R lies within the MH2 domain of the Smad4 protein (UniProt.org). G352R has been identified in the scientific literature (PMID: 23139211, PMID: 15031030), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
K70T missense unknown SMAD4 K70T lies within the MH1 domain of the Smad4 protein (UniProt.org). K70T has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
V492F missense unknown SMAD4 V492F lies within the MH2 domain of the Smad4 protein (UniProt.org). V492F has been identified in sequencing studies (PMID: 15014009, PMID: 22980975), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
R361G missense no effect - predicted SMAD4 R361G lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). R361G results in a slight reduction in BMP signaling in cell culture, but is not significantly different from wild-type Smad4 (PMID: 22316667) and therefore, is predicted to have no effect on Smad4 protein function.
E417* nonsense loss of function - predicted SMAD4 E417* results in a premature truncation of the Smad4 protein at amino acid 417 of 552 (UniProt.org). E417* has not been characterized however, due to the effects of other truncation mutations downstream of E417 (PMID: 11553622, PMID: 22316667), E417* is predicted to lead to a loss of Smad4 protein function.
K45N missense unknown SMAD4 K45N lies within the MH1 domain of the Smad4 protein (UniProt.org). K45N has been identified in the scientific literature (PMID: 23139211), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
K110Nfs*12 frameshift loss of function - predicted SMAD4 K110Nfs*12 indicates a shift in the reading frame starting at amino acid 110 and terminating 12 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). K110Nfs*12 has not been characterized however, due to the effects of other truncation mutations downstream of K110 (PMID: 11553622, PMID: 22316667), K110Nfs*12 is predicted to lead to a loss of Smad4 protein function .
R497H missense loss of function SMAD4 R497H lies in the MH2 domain of the Smad4 protein (UniProt.org). R497H confers a loss of function to the Smad4 protein as demonstrated by reduced transactivating activity and DNA binding in cell assays and acts in a dominant-negative manner (PMID: 14647410).
C324R missense unknown SMAD4 C324R lies within the MH2 domain of the Smad4 protein (UniProt.org). C324R has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
A466fs frameshift loss of function - predicted SMAD4 A466fs results in a change in the amino acid sequence of the Smad4 protein beginning at 466 of 552, likely resulting in premature truncation of the functional protein (UniProt.org). A466fs has not been characterized however, due to the effects of other truncation mutations downstream of A466 (PMID: 11553622, PMID: 22316667), A466fs is predicted to lead to a loss of Smad4 protein function.
C499Y missense unknown SMAD4 C499Y lies within the MH2 domain of the Smad4 protein (UniProt.org). C499Y has been identified in sequencing studies (PMID: 27121310, PMID: 27311873), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D351G missense unknown SMAD4 D351G lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org, PMID: 23139211). D351G has been identified in sequencing studies (PMID: 28348108, PMID: 27545006), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
Q334* nonsense loss of function - predicted SMAD4 Q334* results in a premature truncation of the Smad4 protein at amino acid 334 of 552 (UniProt.org). Q334* has not been characterized however, due to the effects of other truncation mutations downstream of Q334 (PMID: 11553622, PMID: 22316667), Q334* is predicted to lead to a loss of Smad4 protein function.
D351H missense loss of function SMAD4 D351H lies at a hotspot residue in the MH2 domain of the Smad4 protein (UniProt.org, PMID: 23139211). D351H confers a loss of function to the Smad4 protein as demonstrated by reduced nuclear localization, transactivating activity, and growth arrest in cell assays (PMID: 14647410).
R361C missense loss of function SMAD4 R361C lies at a hotspot residue within MH2 domain of the Smad4 protein (UniProt.org). R361C confers a loss of function to the Smad4 protein as demonstrated by reduced Smad4 transactivating activity in cell assays (PMID: 14647410, PMID: 26488212).
Y322H missense unknown SMAD4 Y322H does not lie within any known functional domains of the Smad4 protein (UniProt.org). Y322H has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
R380S missense unknown SMAD4 R380S lies within the MH2 domain of the Smad4 protein (UniProt.org). R380S has been identified in sequencing studies (PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D537G missense unknown SMAD4 D537G lies within the MH2 domain of the Smad4 protein (UniProt.org). D537G has been identified in sequencing studies (PMID: 24951259, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G65E missense unknown SMAD4 G65E lies within the MH1 domain of the Smad4 protein (UniProt.org). G65E has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
P346Lfs*38 frameshift loss of function - predicted SMAD4 P346Lfs*38 indicates a shift in the reading frame starting at amino acid 346 and terminating 38 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org). P346Lfs*38 is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
P544L missense unknown SMAD4 P544L lies within the MH2 domain of the Smad4 protein (UniProt.org). P544L has been identified in sequencing studies (PMID: 26046389), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
E108* nonsense loss of function - predicted SMAD4 E108* results in a premature truncation of the Smad4 protein at amino acid 108 of 552 (UniProt.org). E108* has not been characterized however, due to the effects of other truncation mutations downstream of E108 (PMID: 11553622, PMID: 22316667), E108* is predicted to lead to a loss of Smad4 protein function.
Y322* nonsense loss of function - predicted SMAD4 Y322* results in a premature truncation of the Smad4 protein at amino acid 322 of 552 (UniProt.org). Y322* has not been characterized however, due to the effects of other truncation mutations downstream of Y322 (PMID: 11553622, PMID: 22316667), Y322* is predicted to lead to a loss of Smad4 protein function.
R100G missense unknown SMAD4 R100G lies within the MH1 domain of the Smad4 protein (UniProt.org). R100G has been identified in the scientific literature (PMID: 23139211, PMID: 28870692), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Feb 2019).
T373R missense unknown SMAD4 T373R lies within the MH2 domain of the Smad4 protein (UniProt.org). T373R has not been characterized in the scientific literature and therefore, its effect on Smad4 protein function is unknown (PubMed, Sep 2018).
P130L missense unknown SMAD4 P130L lies within the MH1 domain of the Smad4 protein (UniProt.org). P130L has been identified in sequencing studies (PMID: 27568332), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
H530Tfs*7 frameshift loss of function - predicted SMAD4 H530Tfs*7 (c.1588delC, reported as R530Tfs*7) indicates a shift in the reading frame starting at amino acid 530 and terminating 7 residues downstream causing a premature truncation of the 552 amino acid Smad4 protein (UniProt.org, PMID: 18823382). H530Tfs*7 is predicted to confer a loss of function to the Smad4 protein as demonstrated by reduced BMP signaling in cell culture (PMID: 22316667).
Q311* nonsense loss of function - predicted SMAD4 Q311* results in a premature truncation of the Smad4 protein at amino acid 311 of 552 (UniProt.org). Q311* has not been characterized however, due to the effects of other truncation mutations downstream of Q311 (PMID: 11553622, PMID: 22316667), Q311* is predicted to lead to a loss of Smad4 protein function.
E330A missense loss of function SMAD4 E330A lies lies within the MH2 domain of the Smad4 protein (UniProt.org). E330A impairs Smad4 transcriptional activity upon Tgf-beta stimulation (PMID: 17994767, PMID: 26488212).
A379T missense unknown SMAD4 A379T lies in the MH2 domain of the Smad4 protein (UniProt.org). A379T has been identified in sequencing studies (PMID: 10451707), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D537E missense loss of function SMAD4 D537E lies within the MH2 domain of the Smad4 protein (UniProt.org). D537E confers a loss of function to the Smad4 protein as demonstrated by disruption of Smad4 homo- and hetero-oligomerization and failure to translocate to the nucleus upon TGF-beta stimulation in cell culture (PMID: 9214508, PMID: 11265759).
P356R missense unknown SMAD4 P356R lies within the MH2 domain of the Smad4 protein (UniProt.org). P356R has been identified in sequencing studies (PMID: 29117359, PMID: 29152076), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
G386S missense unknown SMAD4 G386S lies within the MH2 domain of the Smad4 protein (UniProt.org). G386S has been identified in sequencing studies (PMID: 29360550, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown (PubMed, Aug 2018).
D52Rfs*2 frameshift loss of function - predicted SMAD4 D52Rfs*2 indicates a shift in the reading frame starting at amino acid 52 and terminating 2 residues downstream, resulting in premature truncation of the 552 aa Smad4 protein (UniProt.org). D52Rfs*2 has not been characterized however, due to the effects of other truncation mutations downstream of D52 (PMID: 11553622, PMID: 22316667), D52Rfs*2 is predicted to lead to a loss of Smad4 protein function.
L529fs frameshift loss of function - predicted SMAD4 L529fs results in a change in the amino acid sequence of the Smad4 protein beginning at 529 of 552, likely resulting in premature truncation of the functional protein (UniProt.org). L529fs has not been characterized however, due to the effects of other truncation mutations downstream of L529 (PMID: 11553622, PMID: 22316667), L529fs is predicted to lead to a loss of Smad4 protein function.
Molecular Profile Protein Effect Treatment Approaches
SMAD4 H132Tfs*15 loss of function - predicted
SMAD4 P102L loss of function
SMAD4 L57V unknown
SMAD4 E330K unknown
SMAD4 I383R unknown
SMAD4 P246R unknown
SMAD4 F505Y unknown
SMAD4 G419W unknown
SMAD4 K507A loss of function
SMAD4 E330G no effect - predicted
SMAD4 D537H no effect - predicted
SMAD4 S144* loss of function - predicted
SMAD4 A226T no effect - predicted
SMAD4 D351Y unknown
SMAD4 inact mut loss of function
SMAD4 G510E unknown
SMAD4 R420C unknown
SMAD4 K436N no effect - predicted
SMAD4 V44G unknown
SMAD4 dec exp no effect
SMAD4 G65V loss of function - predicted
SMAD4 W524C unknown
SMAD4 H382L unknown
SMAD4 Q448fs loss of function - predicted
SMAD4 E526K unknown
SMAD4 G386V unknown
CDKN2A mut MET del exon14 PDGFRA mut SMAD4 Q249H
SMAD4 Q249H unknown
SMAD4 D415Efs*20 loss of function - predicted
SMAD4 W99C unknown
SMAD4 A452T unknown
SMAD4 D355G unknown
SMAD4 E526* loss of function - predicted
SMAD4 D493N unknown
SMAD4 G65R unknown
SMAD4 R380K unknown
SMAD4 L98F unknown
SMAD4 A460S unknown
SMAD4 L43S loss of function
SMAD4 P130Q unknown
SMAD4 R515T unknown
SMAD4 E167fs loss of function - predicted
SMAD4 G419R unknown
SMAD4 K519N unknown
SMAD4 D537Y loss of function
SMAD4 wild-type no effect
SMAD4 P91S unknown
SMAD4 A60P unknown
SMAD4 R135* loss of function - predicted
SMAD4 R361S no effect - predicted
SMAD4 H132Y loss of function - predicted
SMAD4 K507R loss of function
SMAD4 E526A unknown
SMAD4 L367P unknown
SMAD4 A457S unknown
SMAD4 K340N unknown
SMAD4 L43V loss of function
SMAD4 W524R unknown
SMAD4 G299R unknown
SMAD4 C324Y gain of function
SMAD4 D355V unknown
SMAD4 L495P unknown
SMAD4 G510V unknown
SMAD4 Y133N unknown
SMAD4 A406T loss of function - predicted
SMAD4 D355N unknown
SMAD4 W509G unknown
SMAD4 S178* loss of function - predicted
SMAD4 Q245* loss of function - predicted
SMAD4 E538K unknown
SMAD4 R361H unknown
SMAD4 E161K unknown
SMAD4 P130S loss of function
SMAD4 G352V unknown
SMAD4 C499R unknown
SMAD4 R531Q unknown
SMAD4 G231Afs*10 loss of function - predicted
SMAD4 P356L unknown
SMAD4 E538* unknown
SMAD4 G386D loss of function - predicted
SMAD4 D494Y unknown
SMAD4 R515G loss of function
SMAD4 Y133H unknown
SMAD4 R445* loss of function - predicted
SMAD4 del loss of function
SMAD4 S343* loss of function - predicted
SMAD4 W509R no effect - predicted
SMAD4 L536Qfs*16 unknown
SMAD4 L104F unknown
SMAD4 E417Sfs*11 loss of function - predicted
SMAD4 Q388* loss of function - predicted
SMAD4 L536P unknown
SMAD4 K507Q loss of function
SMAD4 R100W unknown
SMAD4 R496H loss of function - predicted
SMAD4 L536Q unknown
SMAD4 D493A loss of function - predicted
SMAD4 L540H unknown
SMAD4 L540R loss of function - predicted
SMAD4 E337K unknown
SMAD4 K428T unknown
SMAD4 R361P unknown
SMAD4 A433T unknown
SMAD4 A532V unknown
SMAD4 P356delinsQK unknown
SMAD4 V437D unknown
SMAD4 E526V unknown
SMAD4 L172M unknown
SMAD4 L533R unknown
SMAD4 W524S unknown
SMAD4 C363Y unknown
SMAD4 H382D unknown
SMAD4 P356S unknown
SMAD4 R97H unknown
SMAD4 Y353N unknown
SMAD4 R76K unknown
SMAD4 R100T loss of function
SMAD4 V465M no effect - predicted
SMAD4 R189C unknown
SMAD4 W398* loss of function - predicted
SMAD4 Q83* loss of function - predicted
EML4-ALK CDKN2A del FGFR1 T141R SMAD4 Q83*
SMAD4 L109Q unknown
SMAD4 L109R unknown
SMAD4 A451Lfs*17 loss of function - predicted
SMAD4 W509* loss of function - predicted
SMAD4 E134K unknown
SMAD4 H92Y unknown
SMAD4 P203Hfs*38 loss of function - predicted
SMAD4 G352A unknown
SMAD4 G80R unknown
SMAD4 G386C unknown
SMAD4 A118V unknown
SMAD4 G252* loss of function
SMAD4 G510R unknown
SMAD4 mutant unknown
PTEN mut RB1 mut SMAD4 mut TP53 mut
SMAD4 P470H unknown
SMAD4 G419V loss of function - predicted
SMAD4 G510Dfs*27 loss of function - predicted
SMAD4 H541Y unknown
SMAD4 loss loss of function
SMAD4 D351N unknown
SMAD4 Y353H unknown
SMAD4 A327V unknown
SMAD4 S368C unknown
SMAD4 S504R unknown
SMAD4 D351A unknown
SMAD4 D537V unknown
SMAD4 G352R unknown
SMAD4 K70T unknown
SMAD4 V492F unknown
SMAD4 R361G no effect - predicted
SMAD4 E417* loss of function - predicted
SMAD4 K45N unknown
SMAD4 K110Nfs*12 loss of function - predicted
SMAD4 R497H loss of function
SMAD4 C324R unknown
SMAD4 A466fs loss of function - predicted
SMAD4 C499Y unknown
SMAD4 D351G unknown
SMAD4 Q334* loss of function - predicted
SMAD4 D351H loss of function
SMAD4 R361C loss of function
SMAD4 Y322H unknown
SMAD4 R380S unknown
SMAD4 D537G unknown
SMAD4 G65E unknown
SMAD4 P346Lfs*38 loss of function - predicted
SMAD4 P544L unknown
SMAD4 E108* loss of function - predicted
SMAD4 Y322* loss of function - predicted
SMAD4 R100G unknown
SMAD4 T373R unknown
SMAD4 P130L unknown
SMAD4 H530Tfs*7 loss of function - predicted
SMAD4 Q311* loss of function - predicted
SMAD4 E330A loss of function
SMAD4 A379T unknown
SMAD4 D537E loss of function
SMAD4 P356R unknown
SMAD4 G386S unknown
SMAD4 D52Rfs*2 loss of function - predicted
SMAD4 L529fs loss of function - predicted
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMAD4 inact mut pancreatic cancer sensitive Irinotecan Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring inactivated SMAD4 (mutations or deletion) displayed 4.5-fold greater sensitivity to irinotecan in vitro than wild-type (PMID: 22753594). 22753594
SMAD4 dec exp colorectal cancer not applicable N/A Clinical Study Prognostic In clinical and meta-analyses, decreased expression of Smad4 was correlated with poor prognosis in colorectal cancer (PMID: 25749173, PMID: 19478385, PMID: 25681512, PMID: 26861460). 25749173 19478385 26861460 25681512
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + U0126 Preclinical - Cell culture Actionable In a preclinical study, addition of U0126 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 demonstrated modest inhibition of Mapk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp pancreatic cancer not applicable N/A Clinical Study Prognostic In clinical and meta-analyses, loss of Smad4 expression and SMAD4 inactivating mutations were associated with decreased survival in patients with pancreatic cancer (PMID: 26947875, PMID: 25760429, PMID: 22504380, PMID: 19584151). 22504380 19584151 25760429 26947875
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + SP600125 Preclinical - Cell culture Actionable In a preclinical study, addition of SP600125 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma resistant Cetuximab Clinical Study Actionable In a clinical study, decreased Smad4 expression level correlated with Erbitux (cetuximab) resistance in head and neck squamous cell carcinoma (HNSCC) patients, which is consistent with cell culture studies demonstrating Erbitux (cetuximab) resistance induced by knocking-down of Smad4 expression in HNSCC cell lines (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response SP600125 Preclinical - Cell culture Actionable In a preclinical study, SP600125 demonstrated modest inhibition of Jnk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
CDKN2A mut MET del exon14 PDGFRA mut SMAD4 Q249H melanoma sensitive Imatinib + Carboplatin + Paclitaxel Clinical Study Actionable In a clinical study, a melanoma patient harboring a PDGFRA mutation, CDKN2A mutation, MET exon 14 splice site mutation, and SMAD4 Q249H demonstrated a 21 month overall survival when treated with a combination of Gleevec (imatinib), Paraplatin (carboplatin), and Taxol (paclitaxel) (PMID: 28514312). 28514312
SMAD4 del pancreatic cancer decreased response Gemcitabine Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring SMAD4 homozygous deletions were half as sensitive to gemcitabine in vitro as wild-type cells (PMID: 22753594). 22753594
SMAD4 del pancreatic cancer sensitive Irinotecan Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring inactivated SMAD4 (mutations or deletion) displayed 4.5-fold greater sensitivity to irinotecan in vitro than wild-type (PMID: 22753594). 22753594
SMAD4 del pancreatic cancer sensitive Cisplatin Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring SMAD4 homozygous deletions were twice as sensitive to cisplatin in vitro as wild-type cells (PMID: 22753594). 22753594
EML4-ALK CDKN2A del FGFR1 T141R SMAD4 Q83* pancreatic ductal adenocarcinoma resistant Crizotinib Clinical Study Actionable In a clinical case study, a pancreatic ductal adenocarcinoma patient harboring EML4-ALK along with CDKN2A deletion, FGFR1 T141R, SMAD4 Q83*, and a TP53 splice site mutation, experienced disease progression after 2 months of Xalkori (crizotinib) treatment, then received Alecensa (alectinib) and remained on treatment for at least 3 months (PMID: 28476735). 28476735
EML4-ALK CDKN2A del FGFR1 T141R SMAD4 Q83* pancreatic ductal adenocarcinoma predicted - sensitive Alectinib Clinical Study Actionable In a clinical case study, a pancreatic ductal adenocarcinoma patient harboring EML4-ALK along with CDKN2A deletion, FGFR1 T141R, SMAD4 Q83*, and a TP53 splice site mutation, experienced disease progression after 2 months of Xalkori (crizotinib) treatment, then received Alecensa (alectinib) and remained on treatment for at least 3 months (PMID: 28476735). 28476735
SMAD4 mutant colorectal cancer no benefit Cetuximab Clinical Study Actionable In a clinical study, Chinese metastatic colorectal cancer patients harboring either a SMAD4 mutation or NF1 mutation did not respond to treatment with Erbitux (cetuximab) and showed a shorter progression-free survival compared to patients with wild-type SMAD4 or wild-type NF1 (PMID: 29703253). 29703253
SMAD4 mutant stomach cancer not applicable N/A Guideline Risk Factor Germline mutations in SMAD4 or BMPR1A result in juvenile polyposis syndrome, which is associated with increased risk of developing gastric cancer (NCCN.org). detail...
PTEN mut RB1 mut SMAD4 mut TP53 mut skin cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, a skin cancer cell line harboring mutations in PTEN, RB1, SMAD4 and TP53 demonstrated sensitivity to Sapanisertib (MLN0128) in culture (PMID: 25261369). 25261369
SMAD4 loss pancreatic carcinoma sensitive SD-093 Preclinical Actionable In a preclinical study, SD-093 reduced the migration and invasiveness of pancreatic carcinoma cell lines lacking Smad4 (PMID: 15289325). 15289325