Is KIT p.Ala280= (c.840G>C) pathogenic?

KIT p.Ala280= (c.840G>C) is classified Benign/Likely benign in KIT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-03). Ultra-rare (popmax 0.014%, nfe); Associated with gastrointestinal stromal tumor.

What condition is associated with KIT p.Ala280= (c.840G>C)?

KIT p.Ala280= (c.840G>C) is associated with gastrointestinal stromal tumor, piebaldism, testicular germ cell tumor (ClinVar).

How common is KIT p.Ala280= (c.840G>C) in the general population?

KIT p.Ala280= (c.840G>C) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

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

KIT p.Ala280=

c.840G>C · rs142772432 · VCV237283

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -4.5, phastCons 0.98
Overall
CADD	5.539	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.014% European (non-Finnish) · 165/1,179,608 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0108% 175/1,613,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.014%	7,149
African / African-American	0.00801%	12,482
Remaining individualsnot grpmax-eligible	0.0064%	15,617

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.Ala280=
Coding: c.840G>C
MANE Select: NM_000222
dbSNP: rs142772432
Type: single nucleotide variant
Location: chr4:54703807 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 280: a disulfide bond; the ig-like c2-type 3 domain

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: piebaldism testicular germ cell tumor hereditary neoplastic syndrome acute myeloid leukemia cutaneous mastocytosis

For Gastrointestinal stromal tumor (Orphanet):

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

Similar variants

KIT p.Ala280Thr Uncertain significance ★ ⚠ same residue
KIT p.Ala280Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala280 (accessed [today's date]).

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