Is KIT p.Arg956Trp (c.2866C>T) pathogenic?

KIT p.Arg956Trp (c.2866C>T) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.2974); Very rare (popmax 0.00892%, eas); Associated with acute myeloid leukemia.

What condition is associated with KIT p.Arg956Trp (c.2866C>T)?

KIT p.Arg956Trp (c.2866C>T) is associated with acute myeloid leukemia, piebaldism, testicular germ cell tumor (ClinVar).

How common is KIT p.Arg956Trp (c.2866C>T) in the general population?

KIT p.Arg956Trp (c.2866C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about KIT p.Arg956Trp (c.2866C>T)?

AlphaMissense predicts likely benign (score 0.2974) — an in-silico prediction, not a clinical call.

KIT p.Arg956Trp

c.2866C>T · rs587778433 · VCV134627

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

acute myeloid leukemia

Computational evidence

Protein change
AlphaMissense	0.2974	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.083	GERP -4.9, phastCons 0.81
Regional constraint	o/e 1.01	unconstrained · MANE · 1,746 bp · p 0.88 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,860 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00291% 47/1,613,892 alleles · very rare exomes 44/1,461,776 · genomes 3/152,116 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,215
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00401%	24,965
European (non-Finnish)	0.00297%	33,713
Admixed American	0.00167%	59,998

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KIT
Protein: p.Arg956Trp
Coding: c.2866C>T
MANE Select: NM_000222
dbSNP: rs587778433
Type: single nucleotide variant
Location: chr4:54738492 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB

Full KIT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acute myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: piebaldism testicular germ cell tumor gastrointestinal stromal tumor hereditary neoplastic syndrome cutaneous mastocytosis

Similar variants

KIT p.Arg956Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
KIT p.Arg956= Likely benign ★ same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp816His Pathogenic ★★ same condition
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Gln190Ter Pathogenic ★★ same condition
KIT p.Leu576Pro Pathogenic/Likely pathogenic ★★ same condition
KIT p.Lys642Glu Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/kit-p-arg956trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown