Is KIT p.Ile527Met (c.1581T>G) pathogenic?

KIT p.Ile527Met (c.1581T>G) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-22). AlphaMissense: likely benign (0.1021); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Ile527Met (c.1581T>G)?

KIT p.Ile527Met (c.1581T>G) is associated with hereditary neoplastic syndrome, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Ile527Met (c.1581T>G) in the general population?

KIT p.Ile527Met (c.1581T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about KIT p.Ile527Met (c.1581T>G)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

KIT p.Ile527Met

c.1581T>G · rs994448695 · VCV1387120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.581	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.06	GERP -4.9, phastCons 0.88
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	18.23	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 0.000254% European (non-Finnish) · 3/1,180,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,054 alleles · very rare

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.Ile527Met
Coding: c.1581T>G
MANE Select: NM_000222
dbSNP: rs994448695
Type: single nucleotide variant
Location: chr4:54727258 (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.Ile527Leu Uncertain significance ★★ ⚠ same residue
KIT p.Ile527= Uncertain significance ★ same residue
KIT p.Ile527Ser Uncertain significance ★ ⚠ same residue
KIT p.Ile527Thr 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

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-ile527met (accessed [today's date]).

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