Is CHEK2 p.Pro393Ser (c.1177C>T) pathogenic?

CHEK2 p.Pro393Ser (c.1177C>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-24). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro393Ser (c.1177C>T)?

CHEK2 p.Pro393Ser (c.1177C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro393Ser (c.1177C>T) in the general population?

CHEK2 p.Pro393Ser (c.1177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Pro393Ser (c.1177C>T)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro393Ser

c.1177C>T · rs2052558087 · VCV1474181

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 4% in CHEK2
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -13.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	28.1	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

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.Pro393Ser
Coding: c.1177C>T
MANE Select: NM_007194
dbSNP: rs2052558087
Type: single nucleotide variant
Location: chr22:28695792 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 393: an α-helix; 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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast carcinoma

Similar variants

CHEK2 p.Pro393Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro393Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro393= Likely benign ★★ same residue
CHEK2 p.Pro393Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro393His Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro393fs Pathogenic ★ same residue
CHEK2 p.Pro393_Val395del Uncertain significance ★ same residue
CHEK2 p.Pro393Thr Uncertain significance ★ ⚠ same residue

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-pro393ser (accessed [today's date]).

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