Is KIT p.Leu576Pro (c.1727T>C) pathogenic?

KIT p.Leu576Pro (c.1727T>C) is classified Pathogenic/Likely pathogenic in KIT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with Autosomal dominant KIT-related disorders.

What condition is associated with KIT p.Leu576Pro (c.1727T>C)?

KIT p.Leu576Pro (c.1727T>C) is associated with Autosomal dominant KIT-related disorders, gastrointestinal stromal tumor, hereditary neoplastic syndrome (ClinVar).

How common is KIT p.Leu576Pro (c.1727T>C) in the general population?

KIT p.Leu576Pro (c.1727T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KIT p.Leu576Pro (c.1727T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

KIT p.Leu576Pro

c.1727T>C · rs121913513 · VCV375919

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Autosomal dominant KIT-related disorders

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 4% in KIT
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -15.41	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 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	29.7	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

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

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Gastrointestinal Stromal Tumor	Imatinib	D	Sensitivity/Response
Lung Non-small Cell Carcinoma	Nilotinib,Imatinib,Dasatinib	D	Sensitivity/Response
Melanoma	Nilotinib,Imatinib,Sorafenib	D	Resistance
Gastrointestinal Stromal Tumor	Sunitinib	C	Resistance
Gastrointestinal Stromal Tumor	Sunitinib	C	Resistance
Cancer	Imatinib,Dasatinib	D	Sensitivity/Response
Melanoma	Dasatinib	D	Sensitivity/Response

Variant & gene context

Gene: KIT
Protein: p.Leu576Pro
Coding: c.1727T>C
MANE Select: NM_000222
dbSNP: rs121913513
Type: single nucleotide variant
Location: chr4:54727495 (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

Autosomal dominant KIT-related disorders

Also linked: gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

KIT p.Leu576Phe Uncertain significance ★ ⚠ same residue
KIT p.Leu576Val Uncertain significance ★ ⚠ same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Gln190Ter Pathogenic ★★ same condition
KIT p.Lys642Glu Pathogenic ★★ same condition
KIT p.Trp557Arg Pathogenic/Likely pathogenic ★★ same condition
KIT p.Val559Ala 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-leu576pro (accessed [today's date]).

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