Is KIT p.Arg686His (c.2057G>A) pathogenic?

KIT p.Arg686His (c.2057G>A) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-29). AlphaMissense: ambiguous (0.4872); Ultra-rare (popmax 0.0133%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Arg686His (c.2057G>A)?

KIT p.Arg686His (c.2057G>A) is associated with hereditary neoplastic syndrome, testicular cancer, mastocytosis (ClinVar).

How common is KIT p.Arg686His (c.2057G>A) in the general population?

KIT p.Arg686His (c.2057G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about KIT p.Arg686His (c.2057G>A)?

AlphaMissense predicts ambiguous (score 0.4872) — an in-silico prediction, not a clinical call.

KIT p.Arg686His

c.2057G>A · rs143772138 · VCV458902

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4872	ambiguous
REVEL	0.711	pathogenic-leaning
SaProt	LLR -10.45	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 4,114 bp · p 4.1e-05 · regional, not allelic
Overall
CADD	29.4	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 0.0133% Admixed American · 8/59,948 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00118% 19/1,613,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,493
South Asian	0.0011%	91,070
European (non-Finnish)	0.000848%	117,977

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.Arg686His
Coding: c.2057G>A
MANE Select: NM_000222
dbSNP: rs143772138
Type: single nucleotide variant
Location: chr4:54729401 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 686: the protein kinase domain; an α-helix

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: testicular cancer mastocytosis piebaldism gastrointestinal stromal tumor acute myeloid leukemia

Similar variants

KIT p.Arg686Leu Uncertain significance ★★ ⚠ same residue
KIT p.Arg686Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
KIT p.Arg686= 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
KIT p.Lys642Glu 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-arg686his (accessed [today's date]).

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