Is KIT p.Arg634Trp (c.1900C>T) pathogenic?

KIT p.Arg634Trp (c.1900C>T) is classified Uncertain significance in KIT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.6682); Very rare (popmax 0.0011%, sas); Associated with gastrointestinal stromal tumor.

What condition is associated with KIT p.Arg634Trp (c.1900C>T)?

KIT p.Arg634Trp (c.1900C>T) is associated with gastrointestinal stromal tumor, piebaldism, testicular germ cell tumor (ClinVar).

How common is KIT p.Arg634Trp (c.1900C>T) in the general population?

KIT p.Arg634Trp (c.1900C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KIT p.Arg634Trp (c.1900C>T)?

AlphaMissense predicts likely pathogenic (score 0.6682) — an in-silico prediction, not a clinical call.

KIT p.Arg634Trp

c.1900C>T · rs144369407 · VCV409732

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
AlphaMissense	0.6682	likely pathogenic
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -0.39, phastCons 0.83
Regional constraint	o/e 0.72	unconstrained · MANE · 4,114 bp · p 4.1e-05 · regional, not allelic
Overall
CADD	26.8	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 0.0011% South Asian · 1/91,084 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000958% 14/1,461,742 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000932%	107,263

Ashkenazi Jewish 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.Arg634Trp
Coding: c.1900C>T
MANE Select: NM_000222
dbSNP: rs144369407
Type: single nucleotide variant
Location: chr4:54728031 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 634: the protein kinase domain; an α-helix

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

Disease context

gastrointestinal stromal tumor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: piebaldism testicular germ cell tumor hereditary neoplastic syndrome acute myeloid leukemia cutaneous mastocytosis

For Gastrointestinal stromal tumor (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

KIT p.Arg634Gln Uncertain significance ★★ ⚠ same residue
KIT p.Arg634Gly Uncertain significance ★★ ⚠ same residue
KIT p.Arg634Leu Uncertain significance ★★ ⚠ same residue
KIT p.Arg634= Likely benign ★ same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp816His Pathogenic ★★ same condition
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Gln190Ter 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-arg634trp (accessed [today's date]).

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