Is CHEK2 p.Ser428Phe (c.1283C>T) pathogenic?

CHEK2 p.Ser428Phe (c.1283C>T) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 41 submitters; last evaluated 2026-05-14). AlphaMissense: likely pathogenic (0.7513); Very rare (popmax 0.00705%, nfe); Associated with prostate cancer, hereditary.

What condition is associated with CHEK2 p.Ser428Phe (c.1283C>T)?

CHEK2 p.Ser428Phe (c.1283C>T) is associated with prostate cancer, hereditary, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Ser428Phe (c.1283C>T) in the general population?

CHEK2 p.Ser428Phe (c.1283C>T) is very rare (popmax 0.00705%, 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.Ser428Phe (c.1283C>T)?

AlphaMissense predicts likely pathogenic (score 0.7513) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser428Phe

c.1283C>T · rs137853011 · VCV5603

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 41 submitters

AlphaMissense

likely pathogenic

0.7513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00705%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

prostate cancer, hereditary

Computational evidence

Protein change
AlphaMissense	0.7513	likely pathogenic
REVEL	0.323	indeterminate
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.41 · evaluated, not missing
Pangolin	Δ0.21	gain · loss 0.16 · 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	26.0	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 0.00705% European (non-Finnish) · 83/1,176,624 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00534%

Overall 0.0276% 444/1,610,148 alleles · very rare exomes 406/1,457,954 · genomes 38/152,194 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.07%	94
Remaining individualsnot grpmax-eligible	0.0658%	1,520
European (non-Finnish)grpmax	0.00705%	14,176
South Asian	0.0044%	22,741
African / African-American	0.00134%	74,842

Ashkenazi Jewish 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.Ser428Phe
Coding: c.1283C>T
MANE Select: NM_007194
dbSNP: rs137853011
Type: single nucleotide variant
Location: chr22:28695219 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 428: the protein kinase domain; a UniProt-annotated variant site (may increase breast cancer risk)

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 breast cancer prostate cancer hereditary neoplastic syndrome hereditary breast carcinoma breast neoplasm 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.Ser428Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser428= Benign/Likely benign ★★ same residue
CHEK2 p.Ser428Cys Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser428fs Pathogenic ★ same residue
CDS1 p.Gln428His 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-ser428phe (accessed [today's date]).

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