Is CHEK2 p.Arg181Cys (c.541C>T) pathogenic?

CHEK2 p.Arg181Cys (c.541C>T) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 28 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.08); Ultra-rare (popmax 0.0494%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Arg181Cys (c.541C>T)?

CHEK2 p.Arg181Cys (c.541C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Arg181Cys (c.541C>T) in the general population?

CHEK2 p.Arg181Cys (c.541C>T) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about CHEK2 p.Arg181Cys (c.541C>T)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

CHEK2 p.Arg181Cys

c.541C>T · rs137853010 · VCV5597

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 28 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.466	indeterminate
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	23.1	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 0.0494% South Asian · 45/91,072 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00806% 130/1,613,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
Admixed American	0.01%	9,990
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00668%	14,962
European (non-Finnish)	0.00585%	17,100

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.Arg181Cys
Coding: c.541C>T
MANE Select: NM_007194
dbSNP: rs137853010
Type: single nucleotide variant
Location: chr22:28725028 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 181: a UniProt-annotated variant site (in prostate cancer; somatic mutation); a β-strand

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 ovarian cancer syndrome hereditary breast carcinoma CHEK2-related cancer predisposition

Similar variants

CHEK2 p.Arg181Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg181Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg181Pro Uncertain significance ★ ⚠ same residue
CDS1 p.Arg181His Uncertain significance ★ ⚠ 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-arg181cys (accessed [today's date]).

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