Is CHEK2 p.Pro426Ser (c.1276C>T) pathogenic?

CHEK2 p.Pro426Ser (c.1276C>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.9968); Very rare (popmax 8.53e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro426Ser (c.1276C>T)?

CHEK2 p.Pro426Ser (c.1276C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro426Ser (c.1276C>T) in the general population?

CHEK2 p.Pro426Ser (c.1276C>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about CHEK2 p.Pro426Ser (c.1276C>T)?

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

CHEK2 p.Pro426Ser

c.1276C>T · rs1555913523 · VCV548774

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

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	0.805	moderately pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.83 · evaluated, not missing
Pangolin	Δ0.22	gain · loss 0.18 · SpliceAI below 0.2 · independent
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	32.0	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 8.53e-05% European (non-Finnish) · 1/1,172,912 alleles

Overall 6.23e-05% 1/1,606,182 alleles · very rare exomes 1/1,453,878 · genomes 0/152,304 · 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.Pro426Ser
Coding: c.1276C>T
MANE Select: NM_007194
dbSNP: rs1555913523
Type: single nucleotide variant
Location: chr22:28695226 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 426: the protein kinase domain

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.Pro426Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro426Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro426His Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro426Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro426Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro426= Likely benign ★ same residue
CHEK2 p.Pro426fs Pathogenic ★ same residue
CHEK2 c.1008+1G>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-pro426ser (accessed [today's date]).

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