Is CHEK2 p.Pro515His (c.1544C>A) pathogenic?

CHEK2 p.Pro515His (c.1544C>A) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-18). AlphaMissense: likely benign (0.1031); No allele count reported in gnomAD v4.1 (AN 1,594,546); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro515His (c.1544C>A)?

CHEK2 p.Pro515His (c.1544C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Pro515His (c.1544C>A) in the general population?

CHEK2 p.Pro515His (c.1544C>A) is no allele count reported in gnomAD v4.1 (AN 1,594,546) (gnomAD).

What do computational predictors say about CHEK2 p.Pro515His (c.1544C>A)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro515His

c.1544C>A · VCV3266965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,594,546)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -10.53	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	29.9	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

No allele count reported in gnomAD v4.1 (AN 1,594,546). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CHEK2
Protein: p.Pro515His
Coding: c.1544C>A
MANE Select: NM_007194
Type: single nucleotide variant
Location: chr22:28687985 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 515: the 'disordered' 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

Similar variants

CHEK2 p.Pro515Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro515Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro515Leu Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro515= Likely benign ★ 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
CHEK2 c.1008+2T>G 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-pro515his (accessed [today's date]).

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