Is CDK12 p.Arg722Cys (c.2164C>T) pathogenic?

CDK12 p.Arg722Cys (c.2164C>T) is classified Uncertain significance in CDK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely pathogenic (0.9761); Very rare (popmax 0.00334%, amr).

How common is CDK12 p.Arg722Cys (c.2164C>T) in the general population?

CDK12 p.Arg722Cys (c.2164C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CDK12 p.Arg722Cys (c.2164C>T)?

AlphaMissense predicts likely pathogenic (score 0.9761) — an in-silico prediction, not a clinical call.

CDK12 p.Arg722Cys

c.2164C>T · VCV3830752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9761	likely pathogenic
REVEL	0.348	indeterminate
SaProt	LLR -12.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 11 kb · p 9.5e-12 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,956 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000548% 8/1,460,826 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,978
South Asian	0.0011%	91,030
European (non-Finnish)	0.000424%	235,837

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.Arg722Cys
Coding: c.2164C>T
MANE Select: NM_016507
Type: single nucleotide variant
Location: chr17:39492806 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB

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

Similar variants

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
CDK12 c.3308-26A>G Likely 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-arg722cys (accessed [today's date]).

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