Is KIT p.Pro911His (c.2732C>A) pathogenic?

KIT p.Pro911His (c.2732C>A) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.7435); Ultra-rare (popmax 0.0198%, sas); Associated with gastrointestinal stromal tumor.

What condition is associated with KIT p.Pro911His (c.2732C>A)?

KIT p.Pro911His (c.2732C>A) is associated with gastrointestinal stromal tumor, hereditary neoplastic syndrome (ClinVar).

How common is KIT p.Pro911His (c.2732C>A) in the general population?

KIT p.Pro911His (c.2732C>A) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KIT p.Pro911His (c.2732C>A)?

AlphaMissense predicts likely pathogenic (score 0.7435) — an in-silico prediction, not a clinical call.

KIT p.Pro911His

c.2732C>A · rs772159767 · VCV458929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7435 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
AlphaMissense	0.7435	likely pathogenic
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,746 bp · p 0.88 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0198% South Asian · 18/91,068 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.0013% 21/1,613,764 alleles · ultra-rare exomes 21/1,461,614 · genomes 0/152,150 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,059
Remaining individualsnot grpmax-eligible	0.0032%	31,247
European (non-Finnish)	8.48e-05%	1,179,791

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.Pro911His
Coding: c.2732C>A
MANE Select: NM_000222
dbSNP: rs772159767
Type: single nucleotide variant
Location: chr4:54737210 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 911: the protein kinase domain; an α-helix

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

Disease context

gastrointestinal stromal tumor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Gastrointestinal stromal tumor (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

KIT p.Pro911Ser Uncertain significance ★★ ⚠ same residue
KIT p.Pro911= Likely benign ★★ same residue
KIT p.Pro911Leu Uncertain significance ★ ⚠ 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-pro911his (accessed [today's date]).

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