Is KIT p.Thr461= (c.1383A>G) pathogenic?

KIT p.Thr461= (c.1383A>G) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-06-03). Rare (popmax 0.26%, nfe); Associated with mastocytosis.

What condition is associated with KIT p.Thr461= (c.1383A>G)?

KIT p.Thr461= (c.1383A>G) is associated with mastocytosis, piebaldism, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Thr461= (c.1383A>G) in the general population?

KIT p.Thr461= (c.1383A>G) is rare (popmax 0.26%, nfe) (gnomAD).

KIT p.Thr461=

c.1383A>G · rs151016327 · VCV237242

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.26%, nfe)

Conditions

mastocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -4.9
Overall
CADD	1.402	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.26% European (non-Finnish) · 3,071/1,179,992 alleles

Filtering AF 0.253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.249%

Overall 0.259% 4,186/1,614,102 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.28%	78
Ashkenazi Jewishnot grpmax-eligible	0.432%	231
European (non-Finnish)grpmax	0.26%	384
Remaining individualsnot grpmax-eligible	0.198%	504
Amishnot grpmax-eligible	0.11%	912
Middle Eastern	0.066%	1,516
Admixed American	0.03%	3,334
African / African-American	0.024%	4,169

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr461=
Coding: c.1383A>G
MANE Select: NM_000222
dbSNP: rs151016327
Type: single nucleotide variant
Location: chr4:54725893 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 461: a β-strand; a disulfide bond; the ig-like c2-type 5 domain

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

Disease context

mastocytosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: piebaldism gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

KIT p.Thr461Arg 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.Leu576Pro Pathogenic/Likely 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-thr461 (accessed [today's date]).

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