UniProtKB/Swiss-Prot P10721: Variant p.Asp816Val

Mast/stem cell growth factor receptor Kit
Gene: KIT
Chromosomal location: 4q11-q12
Variant information

Variant position:  816
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Unclassified
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Aspartate (D) to Valine (V) at position 816 (D816V, p.Asp816Val).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (D) to medium size and hydrophobic (V)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Variant description:  In mast cell leukemia and mastocytosis; somatic mutation; constitutively activated; loss of interaction with MPDZ.
Any additional useful information about the variant.



Sequence information

Variant position:  816
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  976
The length of the canonical sequence.

Location on the sequence:   RNILLTHGRITKICDFGLAR  D IKNDSNYVVKGNARLPVKWM
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Mouse                         RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

Pig                           RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Bovine                        RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Goat                          RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Cat                           RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Dog                           RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Chicken                       RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

Xenopus laevis                RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 26 – 976 Mast/stem cell growth factor receptor Kit
Topological domain 546 – 976 Cytoplasmic
Domain 589 – 937 Protein kinase
Metal binding 797 – 797 Magnesium
Metal binding 810 – 810 Magnesium
Binding site 796 – 796 ATP
Modified residue 821 – 821 Phosphoserine
Modified residue 823 – 823 Phosphotyrosine; by autocatalysis
Alternative sequence 414 – 976 Missing. In isoform 3.
Mutagenesis 823 – 823 Y -> F. No decrease in activity. Leads to autophosphorylation at Tyr-900.


Literature citations

The direct association of the multiple PDZ domain containing proteins (MUPP-1) with the human c-Kit C-terminus is regulated by tyrosine kinase activity.
Mancini A.; Koch A.; Stefan M.; Niemann H.; Tamura T.;
FEBS Lett. 482:54-58(2000)
Cited for: INTERACTION WITH MPDZ; CHARACTERIZATION OF VARIANT VAL-816; MUTAGENESIS OF LYS-623;

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal.
Voisset E.; Lopez S.; Dubreuil P.; De Sepulveda P.;
Blood 110:2593-2599(2007)
Cited for: INTERACTION WITH FES/FPS; CHARACTERIZATION OF VARIANT VAL-816;

The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.
Sun J.; Pedersen M.; Ronnstrand L.;
J. Biol. Chem. 284:11039-11047(2009)
Cited for: FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS AND CELL SURVIVAL; FUNCTION IN PHOSPHORYLATION OF CBL; PHOSPHORYLATION AT TYR-568; TYR-703; TYR-721 AND TYR-936; UBIQUITINATION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT VAL-816;

Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816.
Kim S.Y.; Kang J.J.; Lee H.H.; Kang J.J.; Kim B.; Kim C.G.; Park T.K.; Kang H.;
Biochem. Biophys. Res. Commun. 410:224-228(2011)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ENZYME REGULATION; AUTOPHOSPHORYLATION; SUBUNIT; CHARACTERIZATION OF VARIANT VAL-816;

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
Gajiwala K.S.; Wu J.C.; Christensen J.; Deshmukh G.D.; Diehl W.; DiNitto J.P.; English J.M.; Greig M.J.; He Y.A.; Jacques S.L.; Lunney E.A.; McTigue M.; Molina D.; Quenzer T.; Wells P.A.; Yu X.; Zhang Y.; Zou A.; Emmett M.R.; Marshall A.G.; Zhang H.M.; Demetri G.D.;
Proc. Natl. Acad. Sci. U.S.A. 106:1542-1547(2009)
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 544-935 IN COMPLEX WITH SUNITINIB; CATALYTIC ACTIVITY; AUTOPHOSPHORYLATION; CHARACTERIZATION OF VARIANTS HIS-816 AND VAL-816; ENZYME REGULATION;

Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.
Furitsu T.; Tsujimura T.; Tono T.; Ikeda H.; Kitayama H.; Koshimizu U.; Sugahara H.; Butterfield J.H.; Ashman L.K.; Kanayama Y.; Matsuzawa Y.; Kitamura Y.; Kanakura Y.;
J. Clin. Invest. 92:1736-1744(1993)
Cited for: VARIANT MAST CELL LEUKEMIA VAL-816;

Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis.
Longley B.J. Jr.; Metcalfe D.D.; Tharp M.; Wang X.; Tyrrell L.; Lu S.-Z.; Heitjan D.; Ma Y.;
Proc. Natl. Acad. Sci. U.S.A. 96:1609-1614(1999)
Cited for: VARIANTS MASTOCYTOSIS VAL-816; PHE-816; TYR-816 AND LYS-839; CHARACTERIZATION OF VARIANTS MASTOCYTOSIS VAL-816; PHE-816; TYR-816 AND LYS-839;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.