Is CDK12 p.Arg37Cys (c.109C>T) pathogenic?

CDK12 p.Arg37Cys (c.109C>T) is classified Uncertain significance in CDK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-15). AlphaMissense: ambiguous (0.4234); Very rare (popmax 0.00167%, amr).

How common is CDK12 p.Arg37Cys (c.109C>T) in the general population?

CDK12 p.Arg37Cys (c.109C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDK12 p.Arg37Cys (c.109C>T)?

AlphaMissense predicts ambiguous (score 0.4234) — an in-silico prediction, not a clinical call.

CDK12 p.Arg37Cys

c.109C>T · VCV3830351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4234	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -9.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,924 bp · p 0.17 · regional, not allelic
Overall
CADD	32.0	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 0.00167% Admixed American · 1/60,022 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000889% 13/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
European (non-Finnish)	0.00102%	98,336

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.Arg37Cys
Coding: c.109C>T
MANE Select: NM_016507
Type: single nucleotide variant
Location: chr17:39462180 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB
Residue 37: the 'disordered' region

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

Similar variants

CDK12 p.Arg37Gly Uncertain significance ★ ⚠ same residue
CDK12 p.Arg37Leu 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

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-arg37cys (accessed [today's date]).

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