Is KIT p.Ser251fs (c.753_756del) pathogenic?

KIT p.Ser251fs (c.753756del) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-23). Very rare (popmax 0.00017%, nfe); Associated with KIT-related disorder.

What condition is associated with KIT p.Ser251fs (c.753_756del)?

KIT p.Ser251fs (c.753_756del) is associated with KIT-related disorder, gastrointestinal stromal tumor, hereditary neoplastic syndrome (ClinVar).

How common is KIT p.Ser251fs (c.753_756del) in the general population?

KIT p.Ser251fs (c.753_756del) is very rare (popmax 0.00017%, nfe) (gnomAD).

KIT p.Ser251fs

c.753_756del · rs1553887960 · VCV458966

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

KIT-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP -2.1, phastCons 0.31

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,768 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,600 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.Ser251fs
Coding: c.753_756del
MANE Select: NM_000222
dbSNP: rs1553887960
Type: Deletion
Location: chr4:54699760 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 251: a disulfide bond; the ig-like c2-type 3 domain

Full KIT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KIT-related disorder

Also linked: gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

KIT p.Ser251Gly Uncertain significance ★★ ⚠ same residue
KIT p.Ser251= Likely benign ★★ same residue
KIT p.Asn819fs Pathogenic ★★ same condition
KIT p.Asp579del Pathogenic ★★ same condition
KIT p.Asn945fs Uncertain significance ★★ same condition
KIT p.Asp458_Val459del Uncertain significance ★★ same condition
KIT c.1115+16del Benign/Likely benign ★★ same condition
KIT c.1116-16_1116-14del Likely benign ★★ 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-ser251fs (accessed [today's date]).

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