Is CHEK2 p.Ala459Pro (c.1375G>C) pathogenic?

CHEK2 p.Ala459Pro (c.1375G>C) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-04). AlphaMissense: likely pathogenic (0.9422); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ala459Pro (c.1375G>C)?

CHEK2 p.Ala459Pro (c.1375G>C) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ala459Pro (c.1375G>C) in the general population?

CHEK2 p.Ala459Pro (c.1375G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHEK2 p.Ala459Pro (c.1375G>C)?

AlphaMissense predicts likely pathogenic (score 0.9422) — an in-silico prediction, not a clinical call.

CHEK2 p.Ala459Pro

c.1375G>C · rs769729382 · VCV229847

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9422	likely pathogenic
REVEL	0.622	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.38	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.19 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	34.0	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 · 1/59,956 alleles

Overall 0.000139% 2/1,441,258 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,956
European (non-Finnish)	8.61e-05%	1,161,624

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.Ala459Pro
Coding: c.1375G>C
MANE Select: NM_007194
dbSNP: rs769729382
Type: single nucleotide variant
Location: chr22:28695127 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 459: an α-helix; the protein kinase domain

Full CHEK2 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: hereditary breast carcinoma

Similar variants

CHEK2 p.Ala459Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ala459Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ala459Val Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ala459= Benign/Likely benign ★★ same residue
CHEK2 p.Ala459fs Pathogenic ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T Likely pathogenic ★★ same condition
CHEK2 c.1008+2T>A Likely 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/chek2-p-ala459pro (accessed [today's date]).

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