Is CDK12 p.Thr269= (c.807C>T) pathogenic?

CDK12 p.Thr269= (c.807C>T) is classified Likely benign in CDK12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-25). Very rare (popmax 0.0022%, sas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with CDK12 p.Thr269= (c.807C>T)?

CDK12 p.Thr269= (c.807C>T) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is CDK12 p.Thr269= (c.807C>T) in the general population?

CDK12 p.Thr269= (c.807C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CDK12 p.Thr269=

c.807C>T · rs1222067329 · VCV1678980

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -0.35, phastCons 0.99
Overall
CADD	11.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00031% 5/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000169%	590,019

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: CDK12
Protein: p.Thr269=
Coding: c.807C>T
MANE Select: NM_016507
dbSNP: rs1222067329
Type: single nucleotide variant
Location: chr17:39462878 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB
Residue 269: the 'disordered' region

Full CDK12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

CDK12 p.Thr269Ser Uncertain significance ★ ⚠ same residue
CDK12 c.2108+56T>A Benign/Likely benign ★★ same condition
CDK12 c.2666+17A>C Benign ★★ same condition
CDK12 c.2769-74G>A Benign ★★ same condition
CDK12 c.3308-26A>G Likely benign ★★ same condition
CDK12 p.Arg1008= Likely benign ★★ same condition
CDK12 p.Arg322= Likely benign ★★ same condition
CDK12 p.Ile1131Val Benign/Likely benign ★★ 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/cdk12-p-thr269 (accessed [today's date]).

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