Is KIT p.Val559Phe (c.1675G>T) pathogenic?

KIT p.Val559Phe (c.1675G>T) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-22). AlphaMissense: likely pathogenic (0.9017); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Val559Phe (c.1675G>T)?

KIT p.Val559Phe (c.1675G>T) is associated with hereditary neoplastic syndrome, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Val559Phe (c.1675G>T) in the general population?

KIT p.Val559Phe (c.1675G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KIT p.Val559Phe (c.1675G>T)?

AlphaMissense predicts likely pathogenic (score 0.9017) — an in-silico prediction, not a clinical call.

KIT p.Val559Phe

c.1675G>T · rs121913520 · VCV955935

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9017	likely pathogenic
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -11.62	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	28.9	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 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 6.2e-05% 1/1,614,128 alleles · very rare exomes 1/1,461,828 · genomes 0/152,300 · joint denominator

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.Val559Phe
Coding: c.1675G>T
MANE Select: NM_000222
dbSNP: rs121913520
Type: single nucleotide variant
Location: chr4:54727443 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 559: a β-strand; a UniProt-annotated variant site (in gist; somatic mutation); a UniProt-annotated variant site (in gist)

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.Val559Ala Pathogenic/Likely pathogenic ★★ same residue
KIT p.Val559Ile Uncertain significance ★ ⚠ same residue
KIT p.Val559= Likely benign ★ same residue
KIT p.Val559Asp Pathogenic same residue
KIT p.Val559_Thr574delinsAla Likely pathogenic ★ same residue
KIT p.Val559_Val560del Pathogenic same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp820Tyr 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-val559phe (accessed [today's date]).

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