Is CHEK2 p.Pro182Arg (c.545C>G) pathogenic?

CHEK2 p.Pro182Arg (c.545C>G) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-11). AlphaMissense: likely pathogenic (0.9286); Very rare (popmax 0.00223%, eas); Associated with CHEK2-related cancer predisposition.

What condition is associated with CHEK2 p.Pro182Arg (c.545C>G)?

CHEK2 p.Pro182Arg (c.545C>G) is associated with CHEK2-related cancer predisposition, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Pro182Arg (c.545C>G) in the general population?

CHEK2 p.Pro182Arg (c.545C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHEK2 p.Pro182Arg (c.545C>G)?

AlphaMissense predicts likely pathogenic (score 0.9286) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro182Arg

c.545C>G · rs372168051 · VCV830294

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

CHEK2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.9286	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	25.4	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 0.00223% East Asian · 1/44,846 alleles

Overall 0.000124% 2/1,613,904 alleles · very rare exomes 2/1,461,804 · genomes 0/152,100 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,846
European (non-Finnish)	8.47e-05%	1,179,944

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.Pro182Arg
Coding: c.545C>G
MANE Select: NM_007194
dbSNP: rs372168051
Type: single nucleotide variant
Location: chr22:28725024 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 182: a β-strand

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

CHEK2 p.Pro182Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro182Ala Uncertain significance ★★ same residue
CHEK2 p.Pro182Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro182His Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro182Leu Uncertain significance ★ same residue
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1096-1G>C Likely pathogenic ★★ same condition
CHEK2 c.1461+1G>A Pathogenic/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-pro182arg (accessed [today's date]).

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