Is KIT p.Pro969Leu (c.2906C>T) pathogenic?

KIT p.Pro969Leu (c.2906C>T) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.8296); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Pro969Leu (c.2906C>T)?

KIT p.Pro969Leu (c.2906C>T) is associated with hereditary neoplastic syndrome, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Pro969Leu (c.2906C>T) in the general population?

KIT p.Pro969Leu (c.2906C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KIT p.Pro969Leu (c.2906C>T)?

AlphaMissense predicts likely pathogenic (score 0.8296) — an in-silico prediction, not a clinical call.

KIT p.Pro969Leu

c.2906C>T · rs1560426544 · VCV580494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8296	likely pathogenic
REVEL	0.516	indeterminate
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,746 bp · p 0.88 · regional, not allelic
Overall
CADD	26.5	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 0.00167% Admixed American · 1/60,028 alleles

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,840 · genomes 0/152,286 · joint denominator

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.Pro969Leu
Coding: c.2906C>T
MANE Select: NM_000222
dbSNP: rs1560426544
Type: single nucleotide variant
Location: chr4:54738532 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastrointestinal stromal tumor

Similar variants

KIT p.Pro969Ala Uncertain significance ★★ ⚠ same residue
KIT p.Pro969Ser Uncertain significance ★★ ⚠ same residue
KIT p.Pro969= Benign/Likely benign ★★ same residue
KIT p.Ala621Thr Pathogenic/Likely 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-pro969leu (accessed [today's date]).

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