Is KIT p.Glu514Ter (c.1540G>T) pathogenic?

KIT p.Glu514Ter (c.1540G>T) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-26). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Glu514Ter (c.1540G>T)?

KIT p.Glu514Ter (c.1540G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is KIT p.Glu514Ter (c.1540G>T) in the general population?

KIT p.Glu514Ter (c.1540G>T) is absent from gnomAD v4.1 (gnomAD).

KIT p.Glu514Ter

c.1540G>T · rs1553891472 · VCV444634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 9 of 21
Splicing
SpliceAI	Δ0.92	donor loss · deltas
Pangolin	Δ0.64	loss · gain 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	54.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KIT
Protein: p.Glu514Ter
Coding: c.1540G>T
MANE Select: NM_000222
dbSNP: rs1553891472
Type: single nucleotide variant
Location: chr4:54726050 (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

Similar variants

KIT p.Glu514Lys Uncertain significance ★ ⚠ same residue
KIT p.Glu514= Likely benign ★ same residue
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Leu576Pro Pathogenic/Likely pathogenic ★★ same condition
KIT p.Trp557Arg Pathogenic/Likely pathogenic ★★ same condition
KIT p.Val559Ala Pathogenic/Likely pathogenic ★★ same condition
KIT c.1232-3T>C Uncertain significance ★★ same condition
KIT c.1647+5C>A Uncertain significance ★★ 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-glu514ter (accessed [today's date]).

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