Is KIT p.Thr594Ile (c.1781C>T) pathogenic?

KIT p.Thr594Ile (c.1781C>T) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-05-27). AlphaMissense: likely benign (0.1632); Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Thr594Ile (c.1781C>T)?

KIT p.Thr594Ile (c.1781C>T) is associated with hereditary neoplastic syndrome, mastocytosis, piebaldism (ClinVar).

How common is KIT p.Thr594Ile (c.1781C>T) in the general population?

KIT p.Thr594Ile (c.1781C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about KIT p.Thr594Ile (c.1781C>T)?

AlphaMissense predicts likely benign (score 0.1632) — an in-silico prediction, not a clinical call.

KIT p.Thr594Ile

c.1781C>T · rs375351432 · VCV409793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1632 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1632	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.19	constrained · MANE · 374 bp · p 8.6e-07 · regional, not allelic
Overall
CADD	23.5	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 0.0022% South Asian · 2/91,014 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00105% 17/1,612,442 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,507
Remaining individualsnot grpmax-eligible	0.0016%	62,354
African / African-American	0.00134%	74,884
European (non-Finnish)	0.0011%	90,754

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.Thr594Ile
Coding: c.1781C>T
MANE Select: NM_000222
dbSNP: rs375351432
Type: single nucleotide variant
Location: chr4:54727829 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 594: the protein kinase domain; a β-strand

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.Thr594Pro Uncertain significance ★★ ⚠ same residue
KIT p.Thr594= Likely benign ★★ same residue
KIT p.Thr594Asn Uncertain significance ★ ⚠ same residue
KIT p.Thr594fs 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

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-thr594ile (accessed [today's date]).

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