Is CHEK2 p.Ala104= (c.312C>T) pathogenic?

CHEK2 p.Ala104= (c.312C>T) is classified Likely benign in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-02). Very rare (popmax 0.0011%, sas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ala104= (c.312C>T)?

CHEK2 p.Ala104= (c.312C>T) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ala104= (c.312C>T) in the general population?

CHEK2 p.Ala104= (c.312C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

CHEK2 p.Ala104=

c.312C>T · VCV3669654

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.65, phastCons 1
Overall
CADD	8.299	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,062 alleles

Overall 6.2e-05% 1/1,613,880 alleles · very rare exomes 1/1,461,610 · genomes 0/152,270 · joint denominator

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.Ala104=
Coding: c.312C>T
MANE Select: NM_007194
Type: single nucleotide variant
Location: chr22:28734410 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB

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

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

CHEK2 p.Ala104Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ala104Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ala104Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ala104Val Uncertain significance ★★ ⚠ same residue
CDS1 p.Ile104Val 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

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-ala104 (accessed [today's date]).

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