Is CHEK2 p.Ala453Pro (c.1357G>C) pathogenic?

CHEK2 p.Ala453Pro (c.1357G>C) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-06). AlphaMissense: ambiguous (0.5382); Ultra-rare (popmax 0.0335%, eas); Associated with prostate cancer, hereditary.

What condition is associated with CHEK2 p.Ala453Pro (c.1357G>C)?

CHEK2 p.Ala453Pro (c.1357G>C) is associated with prostate cancer, hereditary, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Ala453Pro (c.1357G>C) in the general population?

CHEK2 p.Ala453Pro (c.1357G>C) is ultra-rare (popmax 0.0335%, eas) (gnomAD).

How is Familial prostate cancer inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHEK2 p.Ala453Pro (c.1357G>C)?

AlphaMissense predicts ambiguous (score 0.5382) — an in-silico prediction, not a clinical call.

CHEK2 p.Ala453Pro

c.1357G>C · rs763395924 · VCV232008

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

ambiguous

0.5382 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

prostate cancer, hereditary

Computational evidence

Protein change
AlphaMissense	0.5382	ambiguous
REVEL	0.016	strongly benign-leaning
SaProt	LLR -10.93	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.76, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	19.71	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 0.0335% East Asian · 15/44,842 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.000932% 15/1,609,314 alleles · ultra-rare exomes 15/1,457,050 · genomes 0/152,264 · 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.Ala453Pro
Coding: c.1357G>C
MANE Select: NM_007194
dbSNP: rs763395924
Type: single nucleotide variant
Location: chr22:28695145 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 453: the protein kinase domain

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

Disease context

prostate cancer, hereditary — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone osteosarcoma hereditary breast ovarian cancer syndrome breast cancer hereditary neoplastic syndrome hereditary breast carcinoma CHEK2-related cancer predisposition

For Familial prostate cancer (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

CHEK2 p.Ala453Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ala453= Likely benign ★ same residue
CHEK2 p.Ala453Thr Likely benign ★ same residue
CHEK2 p.Ala453fs 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
CHEK2 c.1008+2T>G 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-ala453pro (accessed [today's date]).

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