CDK12

Chr 17

cyclin dependent kinase 12

Also known as: CRK7, CRKR, CRKRS

NCBI Gene: 51755 ENSG00000167258 UniProt: Q9NYV4

Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in several processes, including positive regulation of transcription elongation by RNA polymerase II; protein autophosphorylation; and regulation of MAP kinase activity. Located in nuclear speck. Part of cyclin K-CDK12 complex. Biomarker of gastric adenocarcinoma; hepatocellular carcinoma; and stomach cancer. [provided by Alliance of Genome Resources, Apr 2025]

Active trials

Pathogenic / LP

465

ClinVar variants

Pubs (1 yr)

2.5

Missense Z

0.13

LOEUF· LoF intolerant

Clinical Summary— CDK12

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 Pathogenic / Likely Pathogenic· 321 VUS of 465 total submissions

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Clinical Trials

10 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.13LOEUF

pLI 1.000

Z-score 6.92

OE 0.05 (0.02–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.52Z-score

OE missense 0.75 (0.70–0.80)

596 obs / 796.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.05 (0.02–0.13)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.70–0.80)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97

0≤1.21.6

LoF obs/exp: 3 / 61.7Missense obs/exp: 596 / 796.5Syn Z: 0.43

0.2399th %ile

GOF

0.2497th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.13

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

465 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS321

Likely Benign141

Conflicting1

Pathogenic

321

VUS

141

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	0	0	0	0	0
VUS	2	317	2	0	321
Likely Benign	0	8	10	123	141
Benign	0	0	0	0	0
Conflicting	—				1
Total	2	325	14	123	465

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CDK12 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Prostate CancerCDK12 Gene Mutation

RC48 Monotherapy or Combination With Envafolimab for CDK12 Alterations mCRPC With Standard Treatment Failure

RECRUITING

NCT06663007Phase PHASE1, PHASE2Tianjin Medical University Second HospitalStarted 2024-09-24

RC48Envafolimab

Renal Cell CarcinomaMetastatic Renal Cell CarcinomaKidney Cancer

Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations

RECRUITING

NCT03786796Phase PHASE2Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsStarted 2019-06-03

Olaparib

Metastatic Prostate Cancer

High Dose Testosterone for ATM, CDK12 or CHEK2 Altered Prostate Cancers

RECRUITING

NCT05011383Phase PHASE2VA Office of Research and DevelopmentStarted 2021-08-31

High dose testosterone

Prostate CancerMetastatic Castration-resistant Prostate Cancer

Abemaciclib With or Without Atezolizumab for mCRPC

ACTIVE NOT RECRUITING

NCT04751929Phase PHASE2Dana-Farber Cancer InstituteStarted 2021-08-20

AbemaciclibAtezolizumab

Advanced Solid Tumor

A Modular Multi-Basket Trial to Improve Personalized Medicine in Cancer Patients (Basket of Baskets)

RECRUITING

NCT03767075Phase PHASE2Vall d'Hebron Institute of OncologyStarted 2018-12-10

AtezolizumabFutibatinibAmivantamab

Advanced Solid TumorsEwing SarcomaHepatocellular Carcinoma (HCC)

A Phase 1/1B Study of ST-01156, a Small Molecule RBM39 Degrader, in Patients With Advanced Solid Malignancies

RECRUITING

NCT07197554Phase PHASE1SEED Therapeutics, Inc.Started 2025-12-01

ST-01156

Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

RECRUITING

NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14

PalbociclibSunitinibTemsirolimus

Prostate Cancer Metastatic Castration-ResistantAbnormal DNA RepairMetastatic Prostate Carcinoma

Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

ACTIVE NOT RECRUITING

NCT03012321Phase PHASE2Northwestern UniversityStarted 2017-01-12

OlaparibAbiraterone AcetatePrednisone

ATM Gene MutationBRCA1 Gene MutationBRCA2 Gene Mutation

Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects

ACTIVE NOT RECRUITING

NCT04030559Phase PHASE2Marc Dall'Era, MDStarted 2020-02-25

NiraparibNiraparib Tosylate MonohydrateRadical Prostatectomy

Advanced or Metastatic Solid TumorsBreast CancerOvarian Cancer

A Study of PARG Inhibitor IDE161 in Participants With Advanced Solid Tumors

RECRUITING

NCT05787587Phase PHASE1IDEAYA BiosciencesStarted 2023-04-18