Is KIT p.Val374Ile (c.1120G>A) pathogenic?

KIT p.Val374Ile (c.1120G>A) is classified Benign/Likely benign in KIT (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-05-27). AlphaMissense: likely benign (0.0642); Rare (popmax 0.709%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Val374Ile (c.1120G>A)?

KIT p.Val374Ile (c.1120G>A) is associated with hereditary neoplastic syndrome, mastocytosis, piebaldism (ClinVar).

How common is KIT p.Val374Ile (c.1120G>A) in the general population?

KIT p.Val374Ile (c.1120G>A) is rare (popmax 0.709%, afr) (gnomAD).

What do computational predictors say about KIT p.Val374Ile (c.1120G>A)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

KIT p.Val374Ile

c.1120G>A · rs73137716 · VCV237235

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.709%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 32 kb · p 3.4e-16 · regional, not allelic
Overall
CADD	15.94	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.709% African / African-American · 530/74,770 alleles

Filtering AF 0.659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.639%

Overall 0.0394% 632/1,602,326 alleles · rare exomes 334/1,450,074 · genomes 298/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.709%	141
Admixed American	0.055%	1,818
Middle Eastern	0.0496%	2,017
Remaining individualsnot grpmax-eligible	0.029%	3,450
South Asian	0.00771%	12,978
European (non-Finnish)	0.00342%	29,232
East Asian	0.00223%	44,810

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.Val374Ile
Coding: c.1120G>A
MANE Select: NM_000222
dbSNP: rs73137716
Type: single nucleotide variant
Location: chr4:54709428 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 374: a β-strand; the ig-like c2-type 4 domain

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: mastocytosis piebaldism gastrointestinal stromal tumor

Similar variants

KIT p.Val374Ala Uncertain significance ★★ ⚠ same residue
KIT p.Val374Leu Uncertain significance ★ ⚠ same residue
KIT p.Val374= Likely benign ★ 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

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-val374ile (accessed [today's date]).

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