Is CHEK2 p.Ser379Pro (c.1135T>C) pathogenic?

CHEK2 p.Ser379Pro (c.1135T>C) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-29). AlphaMissense: likely pathogenic (0.8995); Very rare (popmax 0.0011%, sas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ser379Pro (c.1135T>C)?

CHEK2 p.Ser379Pro (c.1135T>C) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser379Pro (c.1135T>C) in the general population?

CHEK2 p.Ser379Pro (c.1135T>C) 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.

What do computational predictors say about CHEK2 p.Ser379Pro (c.1135T>C)?

AlphaMissense predicts likely pathogenic (score 0.8995) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser379Pro

c.1135T>C · rs2052562867 · VCV1015524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.8995	likely pathogenic
REVEL	0.385	indeterminate
SaProt	LLR -10.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,064 alleles

Overall 6.84e-05% 1/1,461,486 alleles · very rare

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.Ser379Pro
Coding: c.1135T>C
MANE Select: NM_007194
dbSNP: rs2052562867
Type: single nucleotide variant
Location: chr22:28695834 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 379: an α-helix; a modified residue (phosphoserine; by autocatalysis); the protein kinase domain; the 't-loop/activation segment' region

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.Ser379Cys Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser379Phe Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser379= Benign/Likely benign ★★ same residue
CHEK2 p.Ser379Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser379fs Pathogenic ★ same residue
CHEK2 p.Ser379Thr Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-ser379pro (accessed [today's date]).

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