Is KEAP1 p.Val475Met (c.1423G>A) pathogenic?

KEAP1 p.Val475Met (c.1423G>A) is classified Uncertain significance in KEAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: ambiguous (0.44); Very rare (popmax 0.00167%, amr).

How common is KEAP1 p.Val475Met (c.1423G>A) in the general population?

KEAP1 p.Val475Met (c.1423G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KEAP1 p.Val475Met (c.1423G>A)?

AlphaMissense predicts ambiguous (score 0.44) — an in-silico prediction, not a clinical call.

KEAP1 p.Val475Met

c.1423G>A · rs547713274 · VCV2616427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.44 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.44	ambiguous
REVEL	0.543	indeterminate
SaProt	LLR -11.02	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.35, phastCons 0.97
Regional constraint	o/e 0.73	unconstrained · MANE · 5,271 bp · p 3e-08 · regional, not allelic
Overall
CADD	20.9	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 0.00167% Admixed American · 1/59,912 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,912
African / African-American	0.00133%	75,034
South Asian	0.0011%	91,074
European (non-Finnish)	0.000593%	168,576

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: KEAP1
Protein: p.Val475Met
Coding: c.1423G>A
MANE Select: NM_203500
dbSNP: rs547713274
Type: single nucleotide variant
Location: chr19:10489756 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 90.44 · 122 PDB
Residue 475: a β-strand

Full KEAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KEAP1 p.Ala30= Benign/Likely benign ★★ same type
KEAP1 p.Val31= Benign/Likely benign ★★ same type
KEAP1 p.Ala30Val Uncertain significance ★ ⚠ same type
KEAP1 p.Ala331Val Uncertain significance ★ ⚠ same type
KEAP1 p.Ala376Thr Uncertain significance ★ ⚠ same type
KEAP1 p.Ala407Thr Uncertain significance ★ ⚠ same type
KEAP1 p.Arg15Gln Uncertain significance ★ ⚠ same type
KEAP1 p.Arg326His Uncertain significance ★ ⚠ same type

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/keap1-p-val475met (accessed [today's date]).

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