CDK12

protein-coding

cyclin dependent kinase 12, the group of Cyclin dependent kinases

Gene summary

Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in several processes, including cellular response to estrogen stimulus; negative regulation of intracellular signal transduction; and positive regulation of transcription elongation by RNA polymerase II. 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, Jun 2026]

Previous symbols:

CRKRS

MANE transcript

NM_016507.4

Inheritance

—

ClinVar variants

P:1U:1258B:746

Top phenotype

Hereditary breast ovarian cancer syndrome

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr17:39,461,486-39,567,559

External References & Databases

Ensembl (ENSG00000167258)

Transcript & Mutation Effects

hg38 • Region Span ~106.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tourette syndromeNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDK12 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 1976

Hereditary breast ovarian cancer syndromeTotal: 27

CDK12-related disorderTotal: 22

not providedTotal: 18

Lung adenocarcinomaTotal: 1

Hereditary cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016507.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	716 clinvar	2 clinvar	719
missense		1 clinvar	1245 clinvar	28 clinvar		1274
nonsense			4 clinvar			4
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	1258	744	2	2005

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016507.4	RefSeq	NP_057591.2	14	MANE Select
ENST00000447079.6	Ensembl	ENSP00000398880.4	14	MANE Select
NM_015083.4	RefSeq	NP_055898.1	14	Standard
ENST00000430627.6	Ensembl	ENSP00000407720.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
TP53 Regulates Transcription of DNA Repair Genes
Transcriptional Regulation by TP53

Biological Process

transcription elongation from RNA polymerase II promoter
mRNA processing
protein phosphorylation
RNA splicing
positive regulation of transcription elongation from RNA polymerase II promoter

Molecular Function

protein kinase activity
cyclin-dependent protein serine/threonine kinase activity
protein binding
ATP binding
transcription factor binding

Cellular Component

cyclin-dependent protein kinase holoenzyme complex
nuclear chromatin
fibrillar center
cyclin K-CDK12 complex
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447079
Coding exons: 14
Length: 103397
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.52	596	797	0.748	0.0000403	9639
Missense (PolyPhen)		128	280.02	0.4571		3432
Synonymous	0.430	296	306	0.969	0.0000153	3065
Loss of Function	6.92	3	61.7	0.0486	0.00000357	728

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cyclin-dependent kinase that phosphorylates the C- terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors. {ECO:0000269|PubMed:11683387, ECO:0000269|PubMed:19651820, ECO:0000269|PubMed:20952539, ECO:0000269|PubMed:22012619, ECO:0000269|PubMed:24662513}.;
Disease: DISEASE: Note=Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.;

Recessive Scores

pRec: 0.161

Intolerance Scores

LoFtool: 0.134
RVIS EVS: -1.17
RVIS percentile EVS: 6.06

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.948

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium