Gene Detail

Gene Symbol JAK3
Synonyms JAK-3 | JAK3_HUMAN | JAKL | L-JAK | LJAK
Gene Description JAK3, tyrosine-protein kinase JAK3, is a non-receptor protein tyrosine kinase involved in the interferon-alpha/beta/gamma pathway and is a member of the JAK/STAT signaling pathway (PMID: 15575979). JAK3 gain of function mutations are commonly observed in T-cell leukemias and lymphomas (PMID: 30079384, PMID: 30250904, PMID: 28284718).
Entrez Id 3718
Chromosome 19
Map Location 19p13.11
Canonical Transcript NM_000215

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
P132A missense unknown JAK3 P132A lies within the FERM domain of the Jak3 protein (UniProt.org). The functional effect of P132A is conflicting, as P132A does not result in constitutive phosphorylation of Jak3 or downstream Stat5 or Erk, and is not transforming in cell culture, however, P132A promotes tumor formation in mouse models (PMID: 21599579).
V678M missense gain of function JAK3 V678M lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). V678M results in constitutive phosphorylation of Jak3, activation of Stat5 and Erk signaling, and is transforming in cell culture (PMID: 25193870).
L1017M missense gain of function - predicted JAK3 L1017M lies within the JH1 protein kinase domain 2 of the Jak3 protein (UniProt.org). L1017M is predicted to confer a gain of function to the Jak3 protein, as demonstrated by transformation of cells in culture (PMID: 20400977).
L857H missense gain of function - predicted JAK3 L857H lies within the protein kinase domain 2 of the Jak3 proteim (UniProt.org). L857H is predicted to confer a gain of function to the Jak3 protein, as demonstrated by cytokine receptor complex-independent activation of Jak3 in cell culture (PMID: 26446793).
E552Q missense unknown JAK3 E552Q lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). E552Q has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
F569Y missense unknown JAK3 F569Y lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). F569Y has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
G589D missense gain of function - predicted JAK3 G589D lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). G589D is predicted to confer a gain of function to the Jak3 protein, as demonstrated by transformation of cells in culture (PMID: 28284718).
R943C missense unknown JAK3 R943C lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R943C has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
T8M missense unknown JAK3 T8M lies within the cytokine/interferon/growth hormone receptor-interacting region of the Jak3 protein (UniProt.org). T8M has not been characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
S577fs frameshift loss of function - predicted JAK3 S577fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 577 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a significant portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), S577fs is predicted to lead to a loss of Jak3 protein function.
D863E missense unknown JAK3 D863E lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). D863E has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
L586_M592del deletion loss of function - predicted JAK3 L586_M592del results in the deletion of seven amino acids in the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein from amino acids 586 to 592 (PMID: 10629052). L586_M592del is predicted to confer a loss of function to the Jak3 protein, as demonstrated by failure to mediate IL-2-dependent Stat5 activation even though it is constitutively hyperphosphorylated in cell culture (PMID: 10629052).
G1057N missense unknown JAK3 G1057N lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). G1057N has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P1086Q missense unknown JAK3 P1086Q lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). P1086Q has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R948C missense unknown JAK3 R948C lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R948C has been identified in the scientific literature (PMID: 23619167), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
H583Y missense gain of function - predicted JAK3 H583Y lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). H538Y is predicted to confer a gain of function to the Jak3 protein, as demonstrated by transformation of cells in culture (PMID: 28284718).
E958K missense gain of function JAK3 E958K lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). E958K confers a gain of function to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793), activation of Stat5, and is transforming in cell culture (PMID: 26206799).
K556A missense unknown JAK3 K556A lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). K556A results in altered subcellular localization of Jak3 as compared to wild-type protein in cell culture (PMID: 15143194), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
I688F missense unknown JAK3 I688F lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). I688F has been identified in the scientific literature (PMID: 29437595), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
H583N missense unknown JAK3 H583N lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). H583N has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R272H missense no effect JAK3 R272H lies within the FERM domain of the Jak3 protein (UniProt.org). R272H demonstrates phosphorylation of Jak3 similar to wild-type protein and is not transforming in cell culture (PMID: 25193870).
G538D missense unknown JAK3 G538D lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). G538D has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
F711fs frameshift loss of function - predicted JAK3 F711fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 711 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), F711fs is predicted to lead to a loss of Jak3 protein function.
A728fs frameshift loss of function - predicted JAK3 A728fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 728 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the protein kinase domain (PMID: 12351625), A728fs is predicted to lead to a loss of Jak3 protein function.
V718L missense unknown JAK3 V718L lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). V718L has been identified in sequencing studies (PMID: 27282351), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown ((PubMed, Apr 2018).
S1124L missense unknown JAK3 S1124L lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). S1124L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
act mut unknown gain of function JAK3 act mut indicates that this variant results in a gain of function in the Jak3 protein. However, the specific amino acid change has not been identified.
S703fs frameshift loss of function - predicted JAK3 S703fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 703 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), S703fs is predicted to lead to a loss of Jak3 protein function.
V579fs frameshift loss of function - predicted JAK3 V579fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 579 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a significant portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), V579fs is predicted to lead to a loss of Jak3 protein function.
R657Q missense gain of function JAK3 R657Q lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). R657Q confers a gain of function to Jak3, as indicated by phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343, PMID: 20400977).
V715A missense unknown JAK3 V715A lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). V715A has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R1085Q missense unknown JAK3 R1085Q lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R1085Q has not been characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
E694fs frameshift loss of function - predicted JAK3 E694fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 694 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a significant portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), E694fs is predicted to lead to a loss of function.
L527R missense unknown JAK3 L527R lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). L527R has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
Q507L missense unknown JAK3 Q507L does not lie within any known functional domains of the Jak3 protein (UniProt.org). Q507L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P420S missense unknown JAK3 P420S lies within the SH2 domain of the Jak3 protein (UniProt.org). P420S has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R402H missense loss of function - predicted JAK3 R402H lies within the SH2 domain of the Jak3 protein (UniProt.org). R402H is predicted to confer a loss of function to the Jak3 protein, as demonstrated by altered subcellular localization and failure to properly localize the common gamma chain to the cell membrane in cell culture (PMID: 15143194).
E717K missense unknown JAK3 E717K lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). E717K has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
E639K missense loss of function JAK3 E639K lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). E639K confers a loss of function to the Jak3 protein, as demonstrated by failure to mediate IL-2-dependent Stat5 activation in cell culture (PMID: 10629052) and the inability to properly localize to the cell membrane (PMID: 15143194).
D949N missense no effect - predicted JAK3 D949N lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). D949N is predicted to have no effect on Jak3 protein function, as demonstrated by subcellular localization similar to wild-type Jak3 and promotion of cytokine receptor common gamma chain membrane expression in cell culture (PMID: 15143194).
R403H missense no effect JAK3 R403H lies within the SH2 domain of the Jak3 protein (UniProt.org). R403H demonstrates phosphorylation of Jak3 similar to wild-type protein and is not transforming in cell culture (PMID: 25193870).
M576L missense unknown JAK3 M576L lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). M576L has been identified in sequencing studies (PMID: 17252020), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
R918C missense gain of function - predicted JAK3 R918C lies within the JH1 protein kinase domain 2 of the Jak3 protein (UniProt.org). R918C is predicted to confer a gain of function to the Jak3 protein, as demonstrated by transformation of cells in culture (PMID: 20400977).
C1077F missense unknown JAK3 C1077F lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). C1077F has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
Q507P missense gain of function - predicted JAK3 Q507P does not lie within any known functional domains of the Jak3 protein (UniProt.org). Q507P is predicted to confer a gain of function tot he Jak3 protein, as demonstrated by activation of STAT5 transcriptional activity and increased phosphorylation of Stat5b in in-vitro assays (PMID: 24825865).
P84fs frameshift loss of function - predicted JAK3 P84fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 84 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of all known functional domains (PMID: 12351625), P84fs is predicted to lead to a loss of Jak3 protein function.
Q501H missense gain of function JAK3 Q501H does not lie within any known functional domains of the Jak3 protein (UniProt.org). Q501H confers a gain of function to Jak3, as indicated by phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343, PMID: 20400977).
D294G missense unknown JAK3 D294G lies within the FERM domain of the Jak3 protein (UniProt.org). D294G has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
L156P missense gain of function JAK3 L156P lies within the FERM domain of the Jak3 protein (UniProt.org). L156P results in a gain of function of the Jak3 protein as demonstrated by increased protein stability and transformation in cell culture (PMID: 21821710).
L857Q missense gain of function JAK3 L857Q lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L857Q results in constitutive phosphorylation of Jak3, activation of Stat5 and Erk signaling, hyperplasia in animal models, and is transforming in cell culture (PMID: 25193870, PMID: 28852199).
L679V missense unknown JAK3 L679V lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). L679V has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
S989I missense unknown JAK3 S989I lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). S989I has been identified in the scientific literature (PMID: 26415585), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P151R missense unknown JAK3 P151R lies within the FERM domain of the Jak3 protein (UniProt.org). P151R has been identified in sequencing studies (PMID: 17456055), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
Q39fs frameshift loss of function - predicted JAK3 Q39fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 39 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to a loss of all known functional domains (UniProt.org), Q39fs is predicted to lead to a loss of function.
A593T missense unknown JAK3 A593T lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). A593T has been identified in the scientific literature (PMID: 17252020), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
A572T missense gain of function JAK3 A572T lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). A572T results in constitutive phosphorylation of Jak3, activation of Stat5 and Erk signaling, and is transforming in cell culture (PMID: 25193870).
R944H missense unknown JAK3 R944H lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R944H has not been characterized in teh scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
V674F missense unknown JAK3 V674F lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). V674F has been identified in sequencing studies (PMID: 27389054), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
V715I missense unknown JAK3 V715I lies within the protein kinase 1 domain of the Jak3 protein (UniProt.org). V715I has been identified in the scientific literature (PMID: 18559588), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
G969V missense unknown JAK3 G969V lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). G969V has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
E183G missense gain of function JAK3 E183G lies within the FERM domain of the Jak3 protein (UniProt.org). E183G confers a gain of function to the Jak3 protein as demonstrated by increased protein stability compared to wild-type, increased Stat5a phosphorylation, and transformation in cultured cells (PMID: 21821710).
I726fs frameshift loss of function - predicted JAK3 I726fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 726 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), I726fs is predicted to lead to a loss of Jak3 protein function.
Y1023H missense unknown JAK3 Y1023H lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). Y1023H has been identified in sequencing studies (PMID: 26415585), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Jun 2018).
V674A missense gain of function JAK3 V674A lies within the protein kinase 1 domain of the Jak3 protein (UniProt.org). V674A confers a gain of function on the Jak3 protein as demonstrated by increased kinase activity and the ability to transform cells in culture (PMID: 16790275, PMID: 20400977).
G589S missense loss of function - predicted JAK3 G589S lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). G589S is predicted to confer a loss of function to the Jak3 protein, as demonstrated by loss of Jak3 autophosphorylation, but does have normal binding to the cytokine receptor, IL2R-alpha gamma chain (PMID: 14615376).
R40H missense unknown JAK3 R40H lies within the FERM domain of the Jak3 protein (UniProt.org). R40H has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
V678L missense gain of function JAK3 V678L lies within the protein kinase 1 (JH2, pseudokinase) domain of the Jak3 protein (UniProt.org). V678L confers a gain of function to the Jak3 protein, as demonstrated by Stat5 activation and transformation of cells in culture (PMID: 26206799).
E1106G missense no effect JAK3 E1106G lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). E1106G demonstrates phosphorylation of Jak3 similar to wild-type protein and is not transforming in cell culture (PMID: 25193870).
D169E missense loss of function JAK3 D169E lies within the FERM domain of the Jak3 protein (UniProt.org). D169E confers a loss of function to the Jak3 protein, as demonstrated by loss of binding to the IL-2R alpha receptor (PMID: 11741532) and the inability to autophosphorylate Jak3 (PMID: 11741532, PMID: 14615376).
R953* nonsense unknown JAK3 R953* results in a premature truncation of the Jak3 protein at amino acid 953 of 1123 (UniProt.org). R953* has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
V722I missense gain of function JAK3 V722I lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). V722I results in constitutive phosphorylation of Jak3, and activation of downstream signaling in cell culture and in patient samples, and is transforming in cell culture (PMID: 23689514, PMID: 16843266).
W709L missense unknown JAK3 W709L lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). W709L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
Y980F missense loss of function JAK3 Y980F lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). Y980F results in impaired Jak3 kinase activity, decreased Stat5 phosphorylation and DNA-binding activity in cell culture (PMID: 9391116).
T848A missense gain of function - predicted JAK3 T848A lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). T848A is predicted to confer a gain of function to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793).
L1091R missense unknown JAK3 L1091R lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L1091R has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R887C missense unknown JAK3 R887C lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R887C has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P906S missense gain of function - predicted JAK3 P906S lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). P906Sis predicted to confer a gain of fucntion to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793).
I87T missense gain of function JAK3 I87T lies within the FERM domain of the Jak3 protein (UniProt.org). I87T confers a gain of function to Jak3, as demonstrated by increased Jak3 autophosphorylation (PMID: 29046866), constitutive phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343).
A573V missense gain of function JAK3 A573V lies within the protein kinase domain of the Jak3 protein (UniProt.org). A573V results in constitutive phosphorylation of Jak3, activation of downstream Stat5 and Erk, is transforming in cultured cells (PMID: 18755984, PMID: 29046866), and induces T-cell acute lymphoblastic leukemia in mouse models (PMID: 25193870).
W709C missense unknown JAK3 W709C lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). W709C has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
K855A missense loss of function JAK3 K855A lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). K855A confers a loss of function to the Jak3 protein, as demonstrated by loss of phosphorylase activity (PMID: 11741532, PMID: 14615376) and the lack of IL-2-dependent Stat5 activation in cell culture (PMID: 10629052) and therefore, is considered a kinase dead mutation (PMID: 29046866).
M576fs frameshift loss of function - predicted JAK3 M576fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 576 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a significant portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), M576fs is predicted to lead to a loss of Jak3 protein function.
S720N missense unknown JAK3 S720N lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). S720N has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
R223H missense unknown JAK3 R223H lies within the FERM domain of the Jak3 protein (UniProt.org). R223H has been identified in sequencing studies (PMID: 26444865), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
C759R missense loss of function JAK3 C759R lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). C759R confers a loss of function to the Jak3 protein, as demonstrated by loss of phosphorylase activity (PMID: 11741532) and the lack of IL-2-dependent Stat5 activation in cell culture (PMID: 10629052).
Q283H missense no effect - predicted JAK3 Q283H lies within the FERM domain of the Jak3 protein (UniProt.org). Q283H is not transforming in cell culture and therefore, is predicted to have no effect on Jak3 protein function (PMID: 26206799).
I688L missense unknown JAK3 I688L lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). I688L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
I535M missense unknown JAK3 I535M lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). I535M has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R657W missense gain of function - predicted JAK3 R657W lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). R657W has not been biochemically characterized, but is predicted to result in a gain of Jak3 function based on the ability to transform cells in culture (PMID: 25193870).
Y100C missense loss of function JAK3 Y100C lies within the FERM domain of the Jak3 protein (UniProt.org). Y100C confers a loss of function to the Jak3 protein, as demonstrated by loss of phosphorylase activity (PMID: 11741532) and also results in a loss of gamma c binding and blocks IL-2-dependent Jak3 activation in cell culture (PMID: 10075926).
M511I missense gain of function JAK3 M511I does not lie within any known functional domains of the Jak3 protein (UniProt.org). M511I results in increased phosphorylation of Jak3, activation of Stat5 and Erk signaling, enhanced tumor growth in animal models, and is transforming in cell culture (PMID: 25193870, PMID: 28852199, PMID: 20400977, PMID: 29046866).
W716* nonsense loss of function - predicted JAK3 W716* results in a premature truncation of the Jak3 protein at amino acid 716 of 1124 (UniProt.org). Due to the loss of most protein kinase domains (UniProt.org), W716* is predicted to lead to a loss of Jak3 protein function.
Q507R missense unknown JAK3 Q507R does not lie within any known functional domains of the Jak3 protein (UniProt.org). Q507R has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R172W missense unknown JAK3 R172W lies within the FERM domain of the Jak3 protein (UniProt.org). R172W has been identified in sequencing studies (PMID: 25822088), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
C162Y missense unknown JAK3 C162Y lies within the FERM domain of the Jak3 protein (UniProt.org). C162Y has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P132T missense gain of function JAK3 P132T lies within the FERM domain of the Jak3 protein (UniProt.org). P132T confers a gain of function to the Jak3 protein, as demonstrated by increased Jak3 autophosphorylation, Stat5 activation (PMID: 29046866), and increased cell proliferation in culture (PMID: 16843266).
G62S missense gain of function JAK3 G62S lies within the FERM domain of the Jak3 protein (UniProt.org). G62S confers a gain of function to the Jak3 protein, as demonstrated by increased autophosphorylation of Jak3, Stat5 activation (PMID: 29046866), and is weakly transforming in cell culture (PMID: 20400977).
P725fs frameshift loss of function - predicted JAK3 P725fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 725 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), P725fs is predicted to lead to a loss of Jak3 protein function.
Q743L missense unknown JAK3 Q743L lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). Q743L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
A58del missense loss of function - predicted JAK3 A58del results in the deletion of one amino acid in the FERM domain of the Jak3 protein at amino acid 58 (UniProt.org). A58del is predicted to confer a loss of function to the Jak3 protein, as demonstrated by loss of Jak3 autophosphorylation, but does have normal binding to the cytokine receptor, IL2R-alpha gamma chain (PMID: 14615376).
L857P missense gain of function JAK3 L857P lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L857P results in cytokine receptor complex-independent activation of Jak3 and increased cell proliferation in culture (PMID: 26446793).
S727fs frameshift loss of function - predicted JAK3 S727fs results in a change in the amino acid sequence of the Jak3 protein beginning at aa 727 of 1124, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of a portion of the protein kinase 1 domain and the entire functional protein kinase 2 domain (PMID: 12351625), S727fs is predicted to lead to a loss of Jak3 protein function.
Y100A missense loss of function JAK3 Y100A lies within the FERM domain of the Jak3 protein (UniProt.org). Y100A confers a loss of function to the Jak3 protein, as demonstrated by a loss of Jak3 kinase activity in cell culture (PMID: 11741532) and the inability to bind the cytokine receptor common gamma-c chains (PMID: 10075926).
L527P missense unknown JAK3 L527P lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). L527P has been identified in sequencing studies (PMID: 17344846), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Oct 2018).
P396L missense unknown JAK3 P396L lies within the SH2 domain of the Jak3 protein (UniProt.org). P396L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
M937T missense unknown JAK3 M937T lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). M937T has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
R172Q missense gain of function JAK3 R172Q lies within the FERM domain of the Jak3 protein (UniProt.org). R172Q confers a gain of function to the Jak3 protein as demonstrated by constitutive autophosphorylation of Jak3 and increased phosphorylation of Stat5a, and is transforming in cultured cells (PMID: 21821710).
wild-type none no effect Wild-type JAK3 indicates that no mutation has been detected within the JAK3 gene.
R925S missense no effect JAK3 R925S lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R925S demonstrates phosphorylation of Jak3 similar to wild-type protein and is not transforming in cell culture (PMID: 25193870).
H1118R missense unknown JAK3 H1118R does not lie within any known functional domains of the Jak3 protein (UniProt.org). H1118R has been identified in the scientific literature (PMID: 23525077), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
A1090T missense unknown JAK3 A1090T lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). A1090T has not been characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
A572V missense gain of function JAK3 A572V lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). A572V confers a gain of function to the Jak3 protein, as demonstrated by increased Jak3 autophosphorylation (PMID: 29046866), constitutive phosphorylation of Jak3 and activation of downstream Stat5 (PMID: 22705984), and leads to cytokine-independent proliferation of cultured cells (PMID: 22705984, PMID: 28284718).
R540H missense unknown JAK3 R540H lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). R540H has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
P975L missense unknown JAK3 P975L lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). P975L has not been characterized in the scientific literature and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2018).
Molecular Profile Protein Effect Treatment Approaches
JAK3 P132A unknown JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 V678M gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 L1017M gain of function - predicted
JAK3 L857H gain of function - predicted JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 E552Q unknown
JAK3 F569Y unknown
JAK3 G589D gain of function - predicted
JAK3 R943C unknown
JAK3 T8M unknown
JAK3 S577fs loss of function - predicted
JAK3 D863E unknown
JAK3 L586_M592del loss of function - predicted
JAK3 G1057N unknown
JAK3 P1086Q unknown
JAK3 R948C unknown
JAK3 H583Y gain of function - predicted
JAK3 E958K gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 K556A unknown
JAK3 I688F unknown
JAK3 H583N unknown
JAK3 R272H no effect
JAK3 G538D unknown
JAK3 F711fs loss of function - predicted
JAK3 A728fs loss of function - predicted
JAK3 V718L unknown
JAK3 S1124L unknown
JAK3 act mut gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 S703fs loss of function - predicted
JAK3 V579fs loss of function - predicted
JAK3 R657Q gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 V715A unknown
JAK3 R1085Q unknown
JAK3 E694fs loss of function - predicted
JAK3 L527R unknown
JAK3 Q507L unknown
JAK3 P420S unknown
JAK3 R402H loss of function - predicted
JAK3 E717K unknown
JAK3 E639K loss of function
JAK3 D949N no effect - predicted
JAK3 R403H no effect
JAK3 M576L unknown
JAK3 R918C gain of function - predicted
JAK3 C1077F unknown
JAK3 Q507P gain of function - predicted
JAK3 P84fs loss of function - predicted
JAK3 Q501H gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 D294G unknown
JAK3 L156P gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 L857Q gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 L679V unknown
JAK3 S989I unknown
JAK3 P151R unknown
JAK3 Q39fs loss of function - predicted
JAK3 A593T unknown
JAK3 A572T gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 R944H unknown
JAK3 V674F unknown
JAK3 V715I unknown
JAK3 G969V unknown
JAK3 E183G gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 I726fs loss of function - predicted
JAK3 Y1023H unknown
JAK3 V674A gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 G589S loss of function - predicted
JAK3 R40H unknown
JAK3 V678L gain of function
JAK3 E1106G no effect
JAK3 D169E loss of function
JAK3 R953* unknown
JAK3 V722I gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 W709L unknown
JAK3 Y980F loss of function
JAK3 T848A gain of function - predicted JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 L1091R unknown
JAK3 R887C unknown
JAK3 P906S gain of function - predicted JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 I87T gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 A573V gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 W709C unknown
JAK3 K855A loss of function
JAK3 M576fs loss of function - predicted
JAK3 S720N unknown
JAK3 R223H unknown
JAK3 C759R loss of function
JAK3 Q283H no effect - predicted
JAK3 I688L unknown
JAK3 I535M unknown
JAK3 R657W gain of function - predicted JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 Y100C loss of function
JAK3 M511I gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 W716* loss of function - predicted
JAK3 Q507R unknown
JAK3 R172W unknown
JAK3 C162Y unknown
JAK3 P132T gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 G62S gain of function
JAK3 P725fs loss of function - predicted
JAK3 Q743L unknown
JAK3 A58del loss of function - predicted
JAK3 L857P JAK3 Y100A
JAK3 L857P gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 S727fs loss of function - predicted
JAK3 Y100A loss of function
JAK3 L527P unknown
JAK3 P396L unknown
JAK3 M937T unknown
JAK3 R172Q gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 wild-type no effect
JAK3 R925S no effect
JAK3 H1118R unknown
JAK3 A1090T unknown
JAK3 A572V gain of function JAK Inhibitor (Pan) JAK Inhibitor (Pan) - ATP competitive JAK3 Inhibitor JAK3 Inhibitor - ATP competitive
JAK3 R540H unknown
JAK3 P975L unknown
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 G589D hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 G589D (PMID: 28284718). 28284718
JAK3 H583Y hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 H538Y (PMID: 28284718). 28284718
JAK3 L156P Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 L156P in culture demonstrated decreased cell survival, increased G1 arrest, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 E183G Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 E183G in culture demonstrated decreased cell survival, increased G1 arrest, elevated apoptotic activity, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 V674A Advanced Solid Tumor sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 V674A in culture (PMID: 26446793). 26446793
JAK3 V674A Advanced Solid Tumor decreased response NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing JAK3 V674A demonstrated reduced sensitivity to NIBR3049 in culture (PMID: 26446793). 26446793
JAK3 V674A Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 V674A in culture (PMID: 26446793). 26446793
JAK3 V722I Advanced Solid Tumor sensitive Tofacitinib Preclinical Actionable In a preclinical study, Xeljanz (tofacitinib) treatment converted cells expressing JAK3 V221I from factor-independent to factor-dependent growth in cell culture (PMID: 25146434). 25146434
JAK3 I87T Advanced Solid Tumor sensitive JANEX-1 Preclinical - Cell culture Actionable In a preclinical study, JANEX-1 (WHI-P131) inhibited proliferation of transformed cells expressing JAK3 I87T in culture (PMID: 18397343). 18397343
JAK3 A573V hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 A573V (PMID: 29046866). 29046866
JAK3 M511I hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 M511I (PMID: 29046866). 29046866
JAK3 L857P JAK3 Y100A Advanced Solid Tumor decreased response Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing both JAK3 L857P and JAK3 Y100A demonstrated reduced sensitivity to Jakafi (ruxolitinib) in culture (PMID: 26446793). 26446793
JAK3 L857P JAK3 Y100A Advanced Solid Tumor sensitive NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, NIBR3049 inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing both JAK3 L857P and Y100A in culture (PMID: 26446793). 26446793
JAK3 L857P JAK3 Y100A Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing both JAK3 L857P and Y100A in culture (PMID: 26446793). 26446793
JAK3 L857P Advanced Solid Tumor decreased response Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing JAK3 L857P demonstrated reduced sensitivity to Jakafi (ruxolitinib) in culture (PMID: 26446793). 26446793
JAK3 L857P Advanced Solid Tumor sensitive NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, NIBR3049 inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 L857P in culture (PMID: 26446793). 26446793
JAK3 L857P Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 L857P in culture (PMID: 26446793). 26446793
JAK3 R172Q Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 R172Q in culture demonstrated decreased cell survival, reduced phosphorylation of Stat5a, and G1 arrest when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 A572V acute myeloid leukemia predicted - resistant NS-108 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring JAK3 A572V was insensitive to treatment with NS-108 in culture (PMID: 22829185). 22829185
JAK3 A572V mature T-cell and NK-cell lymphoma sensitive Tofacitinib Preclinical Actionable In a preclinical study, Xeljanz (tofacitinib), a pan-JAK inhibitor, reduced cell viability and increased apoptosis in a JAK3 A572V mutant natural killer/T-cell lymphoma cell line (PMID: 22705984). 22705984
JAK3 A572V Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 A572V in culture demonstrated decreased cell survival, increased G1 arrest, elevated apoptotic activity, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710