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Gene Symbol SMO
Synonyms CRJS | FZD11 | Gx | SMOH
Gene Description SMO, smoothened, frizzled class receptor, is a G-protein coupled receptor and member of the Hedgehog signaling pathway, which is involved in cell fate, proliferation, and survival (PMID: 16881963). SMO gain-of-function mutations are associated with basal cell carcinoma (PMID: 25085664) and several missense mutations are associated with resistance to Hedgehog pathway inhibitors (PMID: 29175550, PMID: 25306392).

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
A250D missense unknown SMO A250D lies within transmembrane domain 1 of the Smo protein (UniProt.org). A250D has been identified in sequencing studies (PMID: 26960398), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
A324T missense no effect - predicted SMO A324T lies within transmembrane domain 3 of the Smo protein (UniProt.org). A324T has activity similar to wild-type Smo in cultured cells (PMID: 17287906) and therefore, is predicted to have no effect on Smo protein function.
A327P missense loss of function - predicted SMO A327P lies within transmembrane domain 3 of the Smo protein (PMID: 25801792). A327P results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
A338V missense unknown SMO A338V lies within a cytoplasmic domain of the Smo protein (UniProt.org). A338V has been identified in sequencing studies (PMID: 25148578), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
A459V missense gain of function - predicted SMO A459V does not lie within any known functional domains of the Smo protein (UniProt.org). A459V is predicted to confer a gain of function to the Smo protein as demonstrated by increased Smo activity and also confers resistance to Hedgehog inhibitors in cell culture (PMID: 25759019). Y
A729V missense no effect - predicted SMO A729V lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792).. A729V has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785) and therefore, is predicted to have no effect on Smo protein function.
act mut unknown gain of function SMO act mut indicates that this variant results in a gain of function in the Smo protein. However, the specific amino acid change has not been identified.
amp none no effect SMO amp indicates an increased number of copies of the SMO gene. However, the mechanism causing the increase is unspecified.
C169G missense unknown SMO C169G lies within the FZ domain of the Smo protein (UniProt.org). C169G has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
C390R missense loss of function - predicted SMO C390R lies within the ligand-binding pocket of the Smo protein (PMID: 25801792). C390R results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
C469Y missense unknown SMO C469Y lies within the drug-binding pocket of the Smo protein (PMID: 25759019). C469Y has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019). Y
D25G missense unknown SMO D25G lies within the signal peptide region of the Smo protein (UniProt.org). D25G has been identified in the scientific literature (PMID: 23349881, PMID: 26487540), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019).
D384A missense unknown SMO D384A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). D384A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
D384N missense unknown SMO D384N lies within the drug-binding pocket of the Smo protein (PMID: 25759019). D384N has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019). Y
D473G missense no effect - predicted SMO D473G lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473G does not result in activation of Smo, as indicated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, and therefore, is predicted to have no effect on Smo protein function, but has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759020, PMID: 25801792). Y
D473H missense no effect - predicted SMO D473H lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473H shows similar activity to wild-type Smo in cell culture, and therefore, is predicted to have no effect on Smo protein function, but has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 19726788, PMID: 29175550). Y
D473N missense unknown SMO D473N lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473N has not been characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
D473R missense gain of function - predicted SMO D473R lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473R is predicted to confer a gain of function to the Smo protein as demonstrated by increased Gli1 transcription in a reporter assay (PMID: 21123452) and has also been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 21123452). Y
D473Y missense unknown SMO D473Y lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473Y is predicted to confer resistance to Hedgehog pathway inhibitors based on structural modeling (PMID: 2506392), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
D506N missense no effect - predicted SMO D506N lies within an extracellular domain of the Smo protein (UniProt.org). D506N results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
D613N missense no effect - predicted SMO D613N lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). D613N has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
dec exp none no effect SMO dec exp indicates decreased expression of the Smo protein and/or mRNA. However, the mechanism causing the decreased expression is unspecified.
del deletion loss of function SMO del indicates a deletion of the SMO gene.
E181K missense no effect - predicted SMO E181K lies within the FZ domain of the Smo protein (UniProt.org). E181K results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
E194K missense no effect - predicted SMO E194K lies within an extracellular domain of the Smo protein (UniProt.org). E194K has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
E208K missense loss of function - predicted SMO E208K lies within an extracellular domain of the Smo protein (UniProt.org). E208K has not been biochemically characterized, but is predicted to confer a loss of function on the Smo protein as demonstrated by decreased transformation ability in cell culture as compared to wild-type Smo (PMID: 29533785).
E481G missense no effect - predicted SMO E481G lies within the ligand-binding pocket of the Smo protein (PMID: 25801792). E481G results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
E518A missense gain of function - predicted SMO E518A lies within an extracellular domain of the Smo protein (UniProt.org). E518A is predicted to confer a gain of function to the Smo protein as demonstrated by increased Gli1 transcription in a reporter assay (PMID: 21123452) and has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 21123452, PMID: 25008467). Y
E518D missense no effect - predicted SMO E518D lies within an extracellular domain of the Smo protein (UniProt.org). E518D has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
E518K missense unknown SMO E518K lies within an extracellular domain of the Smo protein (UniProt.org). E518K has been described as a resistance mutation (PMID: 21123452), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
F460L missense gain of function - predicted SMO F460L lies within transmembrane domain 6 in the Smo protein (UniProt.org). F460L is predicted to confer a gain of function to the Smo protein as demonstrated by ligand-independent activation of Hedgehog signaling in cell culture and has also been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759020). Y
F605L missense loss of function - predicted SMO F605L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). F605L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
G328V missense no effect - predicted SMO G328V lies within transmembrane domain 3 of the Smo protein (UniProt.org). G328V has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
G453D missense loss of function - predicted SMO G453D lies within transmembrane domain 6 of the Smo protein (Uniprot.org). G453D results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
G497W missense unknown SMO G497W lies within an extracellular domain of the Smo protein (UniProt.org). G497W is predicted to confer resistance to Hedgehog pathway inhibitors based on structural modeling (PMID: 25306392), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
G527E missense no effect - predicted SMO G527E lies within transmembrane domain 7 of the Smo protein (UniProt.org). G527E has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
H227Y missense no effect - predicted SMO H227Y lies within an extracellular domain of the Smo protein (UniProt.org). H227Y has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
H231R missense no effect - predicted SMO H231R lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). H231R is predicted to have no effect on Smo protein function as demonstrated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
H577Q missense unknown SMO H577Q lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). H577Q has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
H577R missense unknown SMO H577R lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). H577R has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
H692fs frameshift unknown SMO H692fs results in a change in the amino acid sequence of the Smo protein beginning at aa 692 of 787, likely resulting in a premature truncation of the functional protein (UniProt.org). H692fs has been identified in sequencing studies (PMID: 29636988), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
I408F missense unknown SMO I408F lies within transmembrane domain 5 of the Smo protein (UniProt.org). I408F has been identified in the scientific literature (PMID: 25636740, PMID: 25008467), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
I408V missense unknown SMO I408V lies within the drug-binding pocket of the Smo protein (PMID: 25759019). I408V has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized, and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019). Y
I637T missense unknown SMO I637T lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). I637T has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
K519R missense gain of function - predicted SMO K519R lies within an extracellular domain of the Smo protein (UniProt.org). K519R results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
K564E missense loss of function - predicted SMO K564E lies within the BBS5 and BBS7-interacting regions of the Smo protein (UniProt.org). K564E results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
K575M missense gain of function - predicted SMO K575M lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). K575M is predicted to confer a gain of function to the Smo protein, as demonstrated by increased expression of the Hedgehog pathway targets PTCH1 and GLI1 in human tumor samples (PMID: 16339184).
L221F missense no effect - predicted SMO L221F lies within an extracellular domain of the Smo protein (UniProt.org). L221F has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
L221P missense loss of function - predicted SMO L221P lies within the ligand-binding pocket of the Smo protein (PMID: 25801792). L221P results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
L221R missense unknown SMO L221R lies within an extracellular domain of the Smo protein (UniProt.org). L221R (corresponding to L225R in mouse) has been demonstrated to confer Hedgehog pathway inhibitor resistance in mouse models (PMID: 20881279), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
L23dup duplication no effect - predicted SMO L23dup (also referred to as L23_G24insL) indicates the insertion of the duplicate amino acid, lysine (L)-23, in in the signal peptide region of the Smo protein (UniProt.org) L23dup has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
L325F missense unknown SMO L325F lies within transmembrane domain 3 of the Smo protein (UniProt.org). L325F has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
L353F missense no effect - predicted SMO L353F lies within a cytoplasmic domain of the Smo protein (UniProt.org). L353F results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
L412F missense gain of function - predicted SMO L412F lies within transmembrane domain 5 in the Smo protein (UniProt.org). L412F is predicted to confer a gain of function to the Smo protein, as indicated by constitutive activation of Hedgehog (Hh) signaling in cell culture and has been demonstrated to confer Hh pathway inhibitor resistance (PMID: 25759020). Y
M525G missense unknown SMO M525G lies within transmembrane domain 7 of the Smo protein (UniProt.org). M525G has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
mutant unknown unknown SMO mutant indicates an unspecified mutation in the SMO gene.
N219D missense unknown SMO N219D lies within the drug-binding pocket of the Smo protein (PMID: 25759019). N219D has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019). Y
N396S missense no effect - predicted SMO N396S lies within an extracellular domain of the Smo protein (UniProt.org). N396S has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
N476K missense no effect - predicted SMO N476K lies within a cytoplasmic domain of the Smo protein (UniProt.org). N476K results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
over exp none no effect SMO over exp indicates an over expression of the Ptch1 protein and/or mRNA. However, the mechanism causing the over expression is unspecified.
P513L missense loss of function - predicted SMO P513L lies within the ligand-binding pocket of the Smo protein (PMID: 25801792). P513L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
P634L missense unknown SMO P634L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P634L has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
P641A missense no effect - predicted SMO P641A lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P641A has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
P647S missense unknown SMO P647S lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P647S has been identified in sequencing studies (PMID: 28195122, PMID: 27624470), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
P688L missense loss of function - predicted SMO P688L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P688L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
P694fs frameshift unknown SMO P694fs results in a change in the amino acid sequence of the Smo protein beginning at aa 694 of 787, likely resulting in a premature truncation of the functional protein (UniProt.org). P694fs has been identified in sequencing studies (PMID: 30239046, PMID: 25344691), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019).
P698T missense no effect - predicted SMO P698T lies within the C-Terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P698T results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
P739L missense loss of function - predicted SMO P739L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P739L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
P739S missense loss of function - predicted SMO P739S lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P739S results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
P753L missense unknown SMO P753L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P753L has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
P768fs frameshift unknown SMO P768fs results in a change in the amino acid sequence of the Smo protein beginning at aa 768 of 787, likely resulting in a premature truncation of the functional protein (UniProt.org). P768fs has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019).
Q477E missense no effect - predicted SMO Q477E lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). Q477E is predicted to have no effect on Smo protein function as demonstrated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
Q635E missense unknown SMO Q635E lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). Q635E has been described as a resistance mutation (PMID: 25759020), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
Q651K missense unknown SMO Q651K lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). Q651K has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R161L missense unknown SMO R161L lies within the FZ domain of the Smo protein (UniProt.org). R161L has been identified in sequencing studies (PMID: 26960398), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R168H missense no effect - predicted SMO R168H lies within the FZ domain of the Smo protein (UniProt.org). R168H results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
R173H missense unknown SMO R173H lies within the FZ domain of the Smo protein (UniProt.org). R173H has been identified in sequencing studies (PMID: 25231023), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Nov 2019).
R199Q missense no effect - predicted SMO R199Q lies within an extracellular domain of the Smo protein (UniProt.org). R199Q results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in cell culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
R199W missense unknown SMO R199W lies within an extracellular domain of the Smo protein (UniProt.org). R199W has been identified in sequencing studies (PMID: 30836094, PMID: 15656799), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R290H missense unknown SMO R290H lies within an extracellular domain of the Smo protein (UniProt.org). R290H has been identified in sequencing studies (PMID: 29854313), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R398Q missense no effect - predicted SMO R398Q lies within an extracellular domain of the Smo protein (UniProt.org). R398Q has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
R400A missense unknown SMO R400A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). R400A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
R400C missense no effect - predicted SMO R400C does not lie within any known functional domains of the Smo protein (UniProt.org). R400C has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
R562Q missense unknown SMO R562Q lies within the BBS5 and BBS7-interacting regions of the Smo protein (UniProt.org). R562Q is transforming in cell culture (PMID: 9422511), but in another study, results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore its effect on Smo protein function is unknown.
R576W missense unknown SMO R576W lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). R576W has not been characterized in the scientific literature and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R628Q missense unknown SMO R628Q lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). R628Q has been identified in sequencing studies (PMID: 25148578), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R628W missense no effect - predicted SMO R628W lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). R628W has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
R726Q missense unknown SMO R726Q lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). R726Q has been identified in the scientific literature (PMID: 23349881, PMID: 30224486), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
R762H missense unknown SMO R762H lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). R762H has been identified in sequencing studies (PMID: 26960396), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
S387A missense unknown SMO S387A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). S387A results in altered cellular localization as demonstrated by increased Smo protein in cell membranes as compared to wild-type in culture (PMID: 25636740), but has not been fully characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
S387N missense unknown SMO S387N lies within the type-I drug-binding site of the Smo protein (PMID: 25636740, PMID: 25759019). S387N has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
S533N missense unknown SMO S533N lies within transmembrane domain 7 of the Smo protein (UniProt.org). S533N (corresponding to S539N in mouse) has been demonstrated to confer resistance to Hedgehog (Hh) pathway inhibitors (PMID: 26546616, PMID: 9581815), and results in increased Hh pathway activation in mouse models and human tumor samples (PMID: 10984056, PMID: 9581815), but also results in similar cell proliferation and viability levels as compared to wild-type Smo in cell culture (PMID: 29533785), and therefore, its effect on Smo protein function is unknown. Y
S574C missense unknown SMO S574C lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). S574C has been identified in sequencing studies (PMID: 22941189), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
T179M missense unknown SMO T179M lies within the FZ domain of the Smo protein (UniProt.org). T179M has been identified in sequencing studies (PMID: 25801821), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
T241M missense gain of function - predicted SMO T241M does not lie within any known functional domains of the Smo protein (UniProt.org). T241M is predicted to confer a gain of function to the Smo protein, as demonstrated by increased Smo activity and also confers resistance to Hedgehog inhibitors in cell culture (PMID: 25759019). Y
T336I missense no effect - predicted SMO T336I lies within a cytoplasmic domain of the Smo protein (UniProt.org). T336I results in similar Hedgehog pathway signaling to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T336P missense no effect - predicted SMO T336P lies within a cytoplasmic domain of the Smo protein (UniProt.org). T336P has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
T349I missense no effect - predicted SMO T349I lies within a cytoplasmic domain of the Smo protein (UniProt.org). T349I results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T349P missense no effect - predicted SMO T349P lies within a cytoplasmic domain of the Smo protein (UniProt.org). T349P results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T466F missense unknown SMO T466F lies within transmembrane domain 6 of the Smo protein (UniProt.org). T466F results in reduced binding to Smo inhibitors as compared to wild-type Smo (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
T534I missense loss of function - predicted SMO T534I lies within transmembrane domain 7 of the Smo protein (UniProt.org). T534I results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
T548I missense no effect - predicted SMO T548I lies within the BBS5 and BBS7-interacting regions of the Smo protein (UniProt.org). T548I results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T640A missense no effect - predicted SMO T640A lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). T640A has activity similar to wild-type Smo in cultured cells (PMID: 17287906, PMID: 25801792) and therefore, is predicted to have no effect on Smo protein function.
V270I missense unknown SMO V270I lies within transmembrane domain 2 of the Smo protein (Uniprot.org). V270I is a common Smo polymorphism (PMID: 23780909, PMID: 23349881), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
V321A missense unknown SMO V321A lies within transmembrane domain 3 of the Smo protein (UniProt.org). V321A has been identified in the scientific literature (PMID: 21123452), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
V321M missense gain of function - predicted SMO V321M lies within transmembrane domain 3 of the Smo protein (UniProt.org). V321M is predicted to confer a gain of function to the Smo protein, as demonstrated by constitutive activation of Hedgehog (Hh) signaling in cell culture and has been demonstrated to confer Hh pathway inhibitor resistance (PMID: 25759020). Y
V329F missense loss of function - predicted SMO V329F lies within transmembrane domain 3 of the Smo protein (UniProt.org). V329F (corresponds to V333F in mouse) results in reduced expression of Gli1 protein and mRNA in cell culture (PMID: 27437577), and demonstrates reduced binding to Smo inhibitors (PMID: 25636740, PMID: 25008467). Y
V386A missense no effect - predicted SMO V386A lies within the ligand-binding pocket of the Smo protein (PMID: 25801792). V386A results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
V404M missense unknown SMO V404M lies within transmembrane domain 5 of the Smo protein (UniProt.org). The functional effect of V404M is conflicting as it demonstrates activity similar to wild-type Smo in culture (PMID: 17287906), but in another study, results in near complete loss of Hedgehog pathway signaling relative to wild-type Smo in culture (PMID: 25801792), and therefore, its effect on Smo protein function is unknown.
V414A missense no effect - predicted SMO V414A lies within transmembrane domain 5 of the Smo protein (UniProt.org). V414A results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and similar cell proliferation and viability levels as wild-type Smo in culture (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
V54M missense no effect - predicted SMO V54M lies within an extracellular domain the Smo protein (UniProt.org). V54M has not been biochemically characterized, but results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
W281C missense no effect - predicted SMO W281C lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). W281C is predicted to have no effect on Smo protein function, as demonstrated by lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
W281L missense unknown SMO W281L lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). W281L has been identified in the scientific literature (PMID: 25199678), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed Apr 2020).
W535L missense unknown SMO W535L lies within the seventh transmembrane domain of the Smo protein (PMID: 9422511). The functional effect of W535L is conflicting, as it results in constitutive activation of Smo and is transforming in cell culture, and has been demonstrated to confer Hedgehog pathway inhibitor resistance (PMID: 9422511, PMID: 10607393, PMID: 25759020), however in another study, W535L results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, its effect on Smo protein function is unknown. Y
W535R missense unknown SMO W535R lies within transmembrane domain 7 of the Smo protein (PMID: 9422511). W535R has been identified in sequencing studies (PMID: 28870692), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
wild-type none no effect Wild-type SMO indicates that no mutation has been detected within the SMO gene.
Y394A missense unknown SMO Y394A lies within the type-I drug-binding site of the Smo protein (PMID: 25636740). Y394A has been demonstrated to confer resistance due to reduced Smo inhibitor binding (PMID: 25636740), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y