Is CHEK2 p.Arg523Ser (c.1567C>A) pathogenic?

CHEK2 p.Arg523Ser (c.1567C>A) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1752); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Arg523Ser (c.1567C>A)?

CHEK2 p.Arg523Ser (c.1567C>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Arg523Ser (c.1567C>A) in the general population?

CHEK2 p.Arg523Ser (c.1567C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Arg523Ser (c.1567C>A)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

CHEK2 p.Arg523Ser

c.1567C>A · rs149501505 · VCV584989

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.15	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 3.4	GERP 0.79, phastCons 0.95
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	14.42	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHEK2
Protein: p.Arg523Ser
Coding: c.1567C>A
MANE Select: NM_007194
dbSNP: rs149501505
Type: single nucleotide variant
Location: chr22:28687962 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 523: the 'disordered' region

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.Arg523Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg523Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg523His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg523Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg523= Likely benign ★ same residue
CHEK2 p.Arg523fs Uncertain significance ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-arg523ser (accessed [today's date]).

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