Is KEAP1 p.Pro408Ser (c.1222C>T) pathogenic?

KEAP1 p.Pro408Ser (c.1222C>T) is classified Likely benign in KEAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.076); Very rare (popmax 0.000344%, nfe).

How common is KEAP1 p.Pro408Ser (c.1222C>T) in the general population?

KEAP1 p.Pro408Ser (c.1222C>T) is very rare (popmax 0.000344%, nfe) (gnomAD).

What do computational predictors say about KEAP1 p.Pro408Ser (c.1222C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

KEAP1 p.Pro408Ser

c.1222C>T · VCV3533255

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000344%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -4.1
Regional constraint	o/e 0.73	unconstrained · MANE · 5,271 bp · p 3e-08 · regional, not allelic
Overall
CADD	7.791	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 0.000344% European (non-Finnish) · 4/1,163,140 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000253% 4/1,578,168 alleles · very rare exomes 4/1,425,784 · genomes 0/152,384 · joint denominator

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.Pro408Ser
Coding: c.1222C>T
MANE Select: NM_203500
Type: single nucleotide variant
Location: chr19:10491680 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 90.44 · 122 PDB
Residue 408: an α-helix

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

Similar variants

KEAP1 p.Pro408Thr Uncertain significance ★ ⚠ same residue
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

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-pro408ser (accessed [today's date]).

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