Is KEAP1 p.Val514Ile (c.1540G>A) pathogenic?

KEAP1 p.Val514Ile (c.1540G>A) is classified Uncertain significance in KEAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely benign (0.1247); Ultra-rare (popmax 0.0418%, sas).

How common is KEAP1 p.Val514Ile (c.1540G>A) in the general population?

KEAP1 p.Val514Ile (c.1540G>A) is ultra-rare (popmax 0.0418%, sas) (gnomAD).

What do computational predictors say about KEAP1 p.Val514Ile (c.1540G>A)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

KEAP1 p.Val514Ile

c.1540G>A · VCV3533256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0418%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -9.96	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 5,271 bp · p 3e-08 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0418% South Asian · 38/90,990 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00415% 67/1,612,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0418%	2,394
Admixed American	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.0112%	8,918
East Asian	0.00223%	44,852
African / African-American	0.00134%	74,890
European (non-Finnish)	0.00102%	98,268

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.Val514Ile
Coding: c.1540G>A
MANE Select: NM_203500
Type: single nucleotide variant
Location: chr19:10489360 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 90.44 · 122 PDB
Residue 514: 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-val514ile (accessed [today's date]).

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