Is CHEK2 p.Pro522= (c.1566C>T) pathogenic?

CHEK2 p.Pro522= (c.1566C>T) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-08). Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro522= (c.1566C>T)?

CHEK2 p.Pro522= (c.1566C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro522= (c.1566C>T) in the general population?

CHEK2 p.Pro522= (c.1566C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

CHEK2 p.Pro522=

c.1566C>T · rs202104749 · VCV184125

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.025	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -1.2, phastCons 0.91
Overall
CADD	4.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,512 alleles

Overall 0.000665% 1/150,392 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.Pro522=
Coding: c.1566C>T
MANE Select: NM_007194
dbSNP: rs202104749
Type: single nucleotide variant
Location: chr22:28687963 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 522: 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

Also linked: hereditary breast carcinoma

Similar variants

CHEK2 p.Pro522Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522His Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522Leu Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Pro522fs 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-pro522 (accessed [today's date]).

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