Is CHEK2 p.Ala17Ser (c.49G>T) pathogenic?

CHEK2 p.Ala17Ser (c.49G>T) is classified Pathogenic in CHEK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-01-01). AlphaMissense: likely benign (0.0617); Absent from gnomAD v4.1; Associated with bone osteosarcoma.

What condition is associated with CHEK2 p.Ala17Ser (c.49G>T)?

CHEK2 p.Ala17Ser (c.49G>T) is associated with bone osteosarcoma (ClinVar).

How common is CHEK2 p.Ala17Ser (c.49G>T) in the general population?

CHEK2 p.Ala17Ser (c.49G>T) 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.Ala17Ser (c.49G>T)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

CHEK2 p.Ala17Ser

c.49G>T · rs137853008 · VCV5595

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

bone osteosarcoma

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign ⚠ discordant with ClinVar
REVEL	0.058	moderately benign-leaning
SaProt	LLR -3.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	0.003	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.Ala17Ser
Coding: c.49G>T
MANE Select: NM_007194
dbSNP: rs137853008
Type: single nucleotide variant
Location: chr22:28734673 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 17: the 'disordered' region; a UniProt-annotated variant site (found in an osteogenic sarcoma sample; somatic mutation; might influence susceptibility to breast cancer)

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

For Osteosarcoma (Orphanet):

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

Similar variants

CHEK2 p.Ala17= Benign/Likely benign ★★ same residue
CHEK2 p.Ala17Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ala17Val Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1461+1G>A 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-ala17ser (accessed [today's date]).

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