Is KIT p.Ile538Val (c.1612A>G) pathogenic?

KIT p.Ile538Val (c.1612A>G) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0588); Very rare (popmax 0.00891%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Ile538Val (c.1612A>G)?

KIT p.Ile538Val (c.1612A>G) is associated with hereditary neoplastic syndrome, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Ile538Val (c.1612A>G) in the general population?

KIT p.Ile538Val (c.1612A>G) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about KIT p.Ile538Val (c.1612A>G)?

AlphaMissense predicts likely benign (score 0.0588) — an in-silico prediction, not a clinical call.

KIT p.Ile538Val

c.1612A>G · rs1560417124 · VCV568265

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0588	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP -4.9, phastCons 0.31
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	11.16	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00891% East Asian · 4/44,884 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,614,168 alleles · very rare exomes 5/1,461,828 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,221
European (non-Finnish)	8.47e-05%	1,179,986

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.Ile538Val
Coding: c.1612A>G
MANE Select: NM_000222
dbSNP: rs1560417124
Type: single nucleotide variant
Location: chr4:54727289 (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.Ile538Leu 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
KIT p.Trp557Arg Pathogenic/Likely pathogenic ★★ same condition
KIT p.Val559Ala Pathogenic/Likely 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-ile538val (accessed [today's date]).

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