Is CHEK2 p.Arg431Ser (c.1293G>T) pathogenic?

CHEK2 p.Arg431Ser (c.1293G>T) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-01-10). AlphaMissense: ambiguous (0.4292); Very rare (popmax 8.48e-05%, nfe).

How common is CHEK2 p.Arg431Ser (c.1293G>T) in the general population?

CHEK2 p.Arg431Ser (c.1293G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CHEK2 p.Arg431Ser (c.1293G>T)?

AlphaMissense predicts ambiguous (score 0.4292) — an in-silico prediction, not a clinical call.

CHEK2 p.Arg431Ser

c.1293G>T · rs587780175 · VCV128055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4292	ambiguous
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.55	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	22.9	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 8.48e-05% European (non-Finnish) · 1/1,178,974 alleles

Overall 6.2e-05% 1/1,612,836 alleles · very rare exomes 1/1,460,594 · genomes 0/152,242 · 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: CHEK2
Protein: p.Arg431Ser
Coding: c.1293G>T
MANE Select: NM_007194
dbSNP: rs587780175
Type: single nucleotide variant
Location: chr22:28695209 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 431: a β-strand; the protein kinase domain

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHEK2 p.Arg431Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg431Met Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg431Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg431= Benign/Likely benign ★★ same residue
CHEK2 p.Arg431Lys Uncertain significance ★ ⚠ same residue
CHEK2 p.Arg431Ter Pathogenic/Likely pathogenic ★★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same type
CHEK2 c.1008+1G>T Likely pathogenic ★★ 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/chek2-p-arg431ser (accessed [today's date]).

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