Is CHEK2 p.Pro509Ser (c.1525C>T) pathogenic?

CHEK2 p.Pro509Ser (c.1525C>T) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 20 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0811); Ultra-rare (popmax 0.0119%, nfe); Associated with prostate cancer, hereditary.

What condition is associated with CHEK2 p.Pro509Ser (c.1525C>T)?

CHEK2 p.Pro509Ser (c.1525C>T) is associated with prostate cancer, hereditary, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Pro509Ser (c.1525C>T) in the general population?

CHEK2 p.Pro509Ser (c.1525C>T) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

How is Familial prostate cancer inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHEK2 p.Pro509Ser (c.1525C>T)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro509Ser

c.1525C>T · rs587780179 · VCV128063

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

prostate cancer, hereditary

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -3.6
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	2.976	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

Grpmax group 0.0119% European (non-Finnish) · 140/1,178,056 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00966%

Overall 0.0102% 162/1,594,024 alleles · ultra-rare exomes 142/1,442,138 · genomes 20/151,886 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0268%	3,733
Remaining individualsnot grpmax-eligible	0.0129%	7,765
European (non-Finnish)grpmax	0.0119%	8,415
African / African-American	0.00134%	74,702

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro509Ser
Coding: c.1525C>T
MANE Select: NM_007194
dbSNP: rs587780179
Type: single nucleotide variant
Location: chr22:28689152 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 509: an α-helix; the 'disordered' region

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

prostate cancer, hereditary — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone osteosarcoma hereditary breast ovarian cancer syndrome colorectal cancer prostate cancer hereditary neoplastic syndrome familial ovarian cancer hereditary breast carcinoma familial colorectal cancer type X hereditary nonpolyposis colon cancer Li-Fraumeni syndrome CHEK2-related cancer predisposition

For Familial prostate cancer (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

CHEK2 p.Pro509His Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro509Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Pro509= Likely benign ★ same residue
CHEK2 p.Pro509fs Likely pathogenic ★ 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-pro509ser (accessed [today's date]).

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