Is CHEK2 p.Ser50Arg (c.148A>C) pathogenic?

CHEK2 p.Ser50Arg (c.148A>C) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.7722); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ser50Arg (c.148A>C)?

CHEK2 p.Ser50Arg (c.148A>C) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser50Arg (c.148A>C) in the general population?

CHEK2 p.Ser50Arg (c.148A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Ser50Arg (c.148A>C)?

AlphaMissense predicts likely pathogenic (score 0.7722) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser50Arg

c.148A>C · rs1569171013 · VCV572799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7722 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7722	likely pathogenic
REVEL	0.155	moderately benign-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	25.8	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.Ser50Arg
Coding: c.148A>C
MANE Select: NM_007194
dbSNP: rs1569171013
Type: single nucleotide variant
Location: chr22:28734574 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 50: 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.Ser50= Benign/Likely benign ★★ same residue
CHEK2 p.Ser50Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser50fs Pathogenic ★ same residue
CDS1 p.Leu50Trp 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-ser50arg (accessed [today's date]).

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