Is CHEK2 p.Thr45= (c.135G>A) pathogenic?

CHEK2 p.Thr45= (c.135G>A) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-31). Very rare (popmax 0.00892%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Thr45= (c.135G>A)?

CHEK2 p.Thr45= (c.135G>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Thr45= (c.135G>A) in the general population?

CHEK2 p.Thr45= (c.135G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

CHEK2 p.Thr45=

c.135G>A · rs745423387 · VCV186358

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.7	GERP -3.1
Overall
CADD	0.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,860 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00118% 19/1,613,720 alleles · very rare exomes 17/1,461,886 · genomes 2/151,834 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,215
South Asian	0.00769%	13,007
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)	0.000593%	168,571

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.Thr45=
Coding: c.135G>A
MANE Select: NM_007194
dbSNP: rs745423387
Type: single nucleotide variant
Location: chr22:28734587 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 45: 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.Thr45Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Thr45Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Thr45Met Uncertain significance ★★ ⚠ same residue
CHEK2 p.Thr45Ser Uncertain significance ★ ⚠ same residue
CHEK2 p.Thr45fs Pathogenic ★★ same residue
CHEK2 p.Thr45Lys Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-thr45 (accessed [today's date]).

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