Is CDK12 p.Ser1096Pro (c.3286T>C) pathogenic?

CDK12 p.Ser1096Pro (c.3286T>C) is classified Likely benign in CDK12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0513); Ultra-rare (popmax 0.0387%, afr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with CDK12 p.Ser1096Pro (c.3286T>C)?

CDK12 p.Ser1096Pro (c.3286T>C) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is CDK12 p.Ser1096Pro (c.3286T>C) in the general population?

CDK12 p.Ser1096Pro (c.3286T>C) is ultra-rare (popmax 0.0387%, afr) (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.

What do computational predictors say about CDK12 p.Ser1096Pro (c.3286T>C)?

AlphaMissense predicts likely benign (score 0.0513) — an in-silico prediction, not a clinical call.

CDK12 p.Ser1096Pro

c.3286T>C · rs144011843 · VCV1678993

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.0513	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 0.94, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 11 kb · p 0.0011 · regional, not allelic
Overall
CADD	17.67	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 0.0387% African / African-American · 29/74,982 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00235% 38/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,586
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed American	0.005%	19,992

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.Ser1096Pro
Coding: c.3286T>C
MANE Select: NM_016507
dbSNP: rs144011843
Type: single nucleotide variant
Location: chr17:39524864 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB
Residue 1096: 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.Ser1096Ala 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-ser1096pro (accessed [today's date]).

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