Is CDK12 p.Glu751= (c.2253A>G) pathogenic?

CDK12 p.Glu751= (c.2253A>G) is classified Likely benign in CDK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). Very rare (popmax 0.0022%, sas).

How common is CDK12 p.Glu751= (c.2253A>G) in the general population?

CDK12 p.Glu751= (c.2253A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

CDK12 p.Glu751=

c.2253A>G · VCV3489365

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

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 3.1	GERP -1.1, phastCons 1
Overall
CADD	8.092	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,038 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,730 alleles · very rare

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.Glu751=
Coding: c.2253A>G
MANE Select: NM_016507
Type: single nucleotide variant
Location: chr17:39494528 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB
Residue 751: the protein kinase domain

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

Similar variants

CDK12 p.Glu751Gln Uncertain significance ★ ⚠ same residue
CDK12 c.2108+56T>A Benign/Likely benign ★★ same type
CDK12 c.2666+17A>C Benign ★★ same type
CDK12 c.2769-74G>A Benign ★★ same type
CDK12 c.2846+157G>T Benign ★★ same type
CDK12 c.2963+111T>A Benign ★★ same type
CDK12 c.2963+133G>A Benign ★★ same type
CDK12 c.3308-116C>T Benign ★★ same type

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-glu751 (accessed [today's date]).

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