Is KIT p.Ala533Val (c.1598C>T) pathogenic?

KIT p.Ala533Val (c.1598C>T) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.2459); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Ala533Val (c.1598C>T)?

KIT p.Ala533Val (c.1598C>T) is associated with hereditary neoplastic syndrome, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Ala533Val (c.1598C>T) in the general population?

KIT p.Ala533Val (c.1598C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about KIT p.Ala533Val (c.1598C>T)?

AlphaMissense predicts likely benign (score 0.2459) — an in-silico prediction, not a clinical call.

KIT p.Ala533Val

c.1598C>T · rs753212327 · VCV2576768

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2459 · 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	0.2459	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	23.7	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) · 3/1,179,998 alleles

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

Overall 0.000205% 3/1,461,834 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.Ala533Val
Coding: c.1598C>T
MANE Select: NM_000222
dbSNP: rs753212327
Type: single nucleotide variant
Location: chr4:54727275 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 533: a UniProt-annotated variant site (in mastc; uncertain significance)

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.Ala533Thr Uncertain significance ★★ ⚠ same residue
KIT p.Ala533Gly Uncertain significance ★ ⚠ same residue
KIT p.Ala533= Likely benign ★ same residue
KIT p.Ala533Asp Pathogenic 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-ala533val (accessed [today's date]).

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