Is CHEK2 p.Ser44Arg (c.132C>A) pathogenic?

CHEK2 p.Ser44Arg (c.132C>A) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-15). AlphaMissense: ambiguous (0.5289); Absent from gnomAD v4.1; Associated with bone osteosarcoma.

What condition is associated with CHEK2 p.Ser44Arg (c.132C>A)?

CHEK2 p.Ser44Arg (c.132C>A) is associated with bone osteosarcoma, CHEK2-related cancer predisposition, prostate cancer, hereditary (ClinVar).

How common is CHEK2 p.Ser44Arg (c.132C>A) in the general population?

CHEK2 p.Ser44Arg (c.132C>A) is absent from gnomAD v4.1 (gnomAD).

How is Osteosarcoma inherited?

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

What do computational predictors say about CHEK2 p.Ser44Arg (c.132C>A)?

AlphaMissense predicts ambiguous (score 0.5289) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser44Arg

c.132C>A · VCV3587875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5289 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

bone osteosarcoma

Computational evidence

Protein change
AlphaMissense	0.5289	ambiguous
REVEL	0.079	moderately benign-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	22.2	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.Ser44Arg
Coding: c.132C>A
MANE Select: NM_007194
Type: single nucleotide variant
Location: chr22:28734590 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 44: the 'disordered' region

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

Disease context

bone osteosarcoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: CHEK2-related cancer predisposition prostate cancer, hereditary

For Osteosarcoma (Orphanet):

Inheritance: Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CHEK2 p.Ser44Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser44= Conflicting classifications of pathogenicity ★ same residue
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1461+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHEK2 c.1462-2A>G Pathogenic/Likely pathogenic ★★ same condition
CHEK2 c.319+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHEK2 c.319+2T>A Pathogenic/Likely pathogenic ★★ same condition
CHEK2 c.444+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-ser44arg (accessed [today's date]).

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