CDK12 (Cyclin-dependent kinase 12) variants and mutations
CDK12 (also known as Cyclin-dependent kinase 12) is a human protein-coding gene encoding a cyclin-dependent kinase 12 protein. It promotes transcription of long DNA-repair and genome-maintenance genes through RNA-polymerase-II phosphorylation. Loss-of-function alterations occur in prostate, ovarian, and other cancers and can create a characteristic pattern of genomic instability. This analysis covers 3,156 CDK12 variants and mutations. Of these, 44% have computational variant effect predictions. Disease context includes prostate adenocarcinoma, neurodegenerative disease, and Alzheimer disease. Example CDK12 variants include P2L, P2S, and N3K.
Variant analysis overview
- Gene: CDK12
- Protein: Cyclin-dependent kinase 12
- UniProt accession: Q9NYV4
- Organism: Homo sapiens
- Variants analyzed: 3156
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 2,978 unspecified-consequence records; 59 missense variants; 101 synonymous variants; 5 frameshift variants; 9 in-frame deletions; 3 in-frame insertions
- Prediction scores: 1,393 variants have prediction scores (44% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: prostate adenocarcinoma, neurodegenerative disease, Alzheimer disease, multiple sclerosis, Parkinson disease, lysosomal storage disease, prostate carcinoma, urinary bladder carcinoma, colon adenocarcinoma, conjunctival intraepithelial neoplasm, skin squamous cell carcinoma, nodular malignant melanoma.
Protein structure and variant hotspots
- Protein features: 1 domains; 4 binding sites; 38 post-translational modification sites.
- Structural context: 563 variants have structural context.
- PTM context: 71 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable CDK12 variants
Examples include P2L, P2S, N3K, S4L, S4P, S4S, E5Q, R6S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- P2L (p.Pro2Leu), Ensembl rs2144845113, REVEL 0.44, CADD 26.30, Uncertain significance, not specified
- P2S (p.Pro2Ser), Ensembl rs2144845060
- N3K (p.Asn3Lys), cosmic curated COSV10825, Ensembl rs2048996662
- S4L (p.Ser4Leu), rs1246755126, ClinGen CA398845737, ClinVar RCV004148493, gnomAD rs1246755126, REVEL 0.28, CADD 26.30, Uncertain significance, not specified
- S4P (p.Ser4Pro), gnomAD 17-39462081-T-C, REVEL 0.13, CADD 20.40
- S4S (p.Ser4Ser), rs745968303, gnomAD 17-39462083-A-G, CADD 10.50
- E5Q (p.Glu5Gln), gnomAD 17-39462084-G-C, REVEL 0.23, CADD 27.30
- R6S (p.Arg6Ser), TOPMed rs957086354
- R6T (p.Arg6Thr), gnomAD rs1191853065, REVEL 0.48, CADD 27.00, Uncertain significance, not specified
- H7D (p.His7Asp), TOPMed rs1477267149, gnomAD rs1477267149, REVEL 0.51, CADD 26.00, Uncertain significance, not specified
- H7R (p.His7Arg), ExAC rs769992254, TOPMed rs769992254, gnomAD rs769992254, REVEL 0.46, CADD 25.60
- H7Y (p.His7Tyr), TOPMed rs1477267149, gnomAD rs1477267149
- H7Q (p.His7Gln), rs1271674731, gnomAD 17-39462091-AT-A, CADD 25.70
- H7H (p.His7His), gnomAD 17-39462092-T-C, CADD 13.10
- G8A (p.Gly8Ala), Ensembl rs2144845879
- G8R (p.Gly8Arg), Ensembl rs2144845805
- G8G (p.Gly8Gly), rs1281679404, gnomAD 17-39462095-G-C, CADD 13.50
- G9D (p.Gly9Asp), cosmic curated COSV10142, gnomAD rs1431644010
- G9S (p.Gly9Ser), gnomAD 17-39462096-G-A, REVEL 0.18, CADD 22.20
- G9V (p.Gly9Val), gnomAD 17-39462097-G-T, REVEL 0.25, CADD 24.20
- G9G (p.Gly9Gly), rs1490354466, gnomAD 17-39462098-C-T, CADD 13.60
- K10R (p.Lys10Arg), ExAC rs779054820, gnomAD rs779054820, REVEL 0.27, CADD 27.00
- K10E (p.Lys10Glu), gnomAD 17-39462099-A-G, REVEL 0.36, CADD 27.20
- K11E (p.Lys11Glu), ExAC rs748073368, gnomAD rs748073368, REVEL 0.36, CADD 27.60
- K11K (p.Lys11Lys), rs144433454, gnomAD 17-39462104-G-A, CADD 12.90
- K11N (p.Lys11Asn), gnomAD 17-39462104-G-C, REVEL 0.28, CADD 25.80
- D12E (p.Asp12Glu), TOPMed rs770631195, Uncertain significance, not specified
- D12D (p.Asp12Asp), rs770631195, gnomAD 17-39462107-C-T, CADD 13.60
- G13E (p.Gly13Glu), Ensembl rs2144846633, REVEL 0.21, CADD 24.10
- G13R (p.Gly13Arg), TOPMed rs1261960315, gnomAD rs1261960315, REVEL 0.20, CADD 27.90, Uncertain significance, not specified
- G13W (p.Gly13Trp), TOPMed rs1261960315, gnomAD rs1261960315
- G13G (p.Gly13Gly), rs773086017, gnomAD 17-39462110-G-C, CADD 13.40
- S14N (p.Ser14Asn), TOPMed rs1295914423, gnomAD rs1295914423, REVEL 0.18, CADD 23.10, Uncertain significance, not specified
- S14R (p.Ser14Arg), TOPMed rs2048999631, REVEL 0.20, CADD 23.40
- S14S (p.Ser14Ser), rs2048999631, gnomAD 17-39462113-T-C, CADD 12.60
- G15R (p.Gly15Arg), gnomAD 17-39462114-G-A, REVEL 0.32, CADD 31.00
- G15G (p.Gly15Gly), gnomAD 17-39462116-A-C, CADD 14.40
- G16A (p.Gly16Ala), ExAC rs760334479, TOPMed rs760334479, gnomAD rs760334479, REVEL 0.21, CADD 24.40, Uncertain significance, not specified
- G16E (p.Gly16Glu), ExAC rs760334479, TOPMed rs760334479, gnomAD rs760334479, REVEL 0.19, CADD 27.50, Uncertain significance, not specified
- G16R (p.Gly16Arg), Ensembl rs2144846928
- G16del (p.Gly16del), gnomAD 17-39462113-TGGA-, CADD 22.20
- A17T (p.Ala17Thr), ExAC rs770630211, gnomAD rs770630211, REVEL 0.18, CADD 24.40
- A17P (p.Ala17Pro), gnomAD 17-39462120-G-C, REVEL 0.21, CADD 25.30
- p.Ala17 Ser18insPhe, gnomAD 17-39462121-C-CCT, CADD 19.90
- S18C (p.Ser18Cys), ExAC rs776079520, TOPMed rs776079520, gnomAD rs776079520, REVEL 0.16, CADD 23.40
- S18F (p.Ser18Phe), ExAC rs776079520, TOPMed rs776079520, gnomAD rs776079520, REVEL 0.22, CADD 24.10, Uncertain significance, not specified
- S18Y (p.Ser18Tyr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S18S (p.Ser18Ser), gnomAD 17-39462125-T-G, CADD 15.40
- G19A (p.Gly19Ala), TOPMed rs1293588243, gnomAD rs1293588243
- G19E (p.Gly19Glu), TOPMed rs1293588243, gnomAD rs1293588243, REVEL 0.27, CADD 27.70
- G19R (p.Gly19Arg), gnomAD 17-39462126-G-A, REVEL 0.30, CADD 28.90
- G19G (p.Gly19Gly), gnomAD 17-39462128-A-C, CADD 15.60
- T20I (p.Thr20Ile), cosmic curated COSV10471, ExAC rs776072090, gnomAD rs776072090, REVEL 0.10, CADD 23.70, Uncertain significance, not specified
- T20P (p.Thr20Pro), gnomAD rs1384681876, REVEL 0.17, CADD 24.20
- T20A (p.Thr20Ala), gnomAD 17-39462129-A-G, REVEL 0.07, CADD 20.70
- L21M (p.Leu21Met), ExAC rs750837447, TOPMed rs750837447, gnomAD rs750837447
- L21L (p.Leu21Leu), rs750837447, gnomAD 17-39462132-T-C, CADD 14.60
- Q22* (p.Gln22Ter), cosmic curated COSV70999, Ensembl rs2144847663
- P23L (p.Pro23Leu), TOPMed rs761257011, gnomAD rs761257011, REVEL 0.12, CADD 26.70, Uncertain significance, not specified
- P23Q (p.Pro23Gln), TOPMed rs761257011, gnomAD rs761257011, REVEL 0.13, CADD 24.10
- P23S (p.Pro23Ser), 1000Genomes rs538322777, Uncertain significance, not specified
- P23R (p.Pro23Arg), gnomAD 17-39462139-C-G, REVEL 0.13, CADD 26.10
- S24* (p.Ser24Ter), Ensembl rs2144848091
- S24A (p.Ser24Ala), ExAC rs753244792, TOPMed rs753244792, gnomAD rs753244792
- S24P (p.Ser24Pro), ExAC rs753244792, TOPMed rs753244792, gnomAD rs753244792, REVEL 0.28, CADD 25.30, Uncertain significance, not specified
- S24L (p.Ser24Leu), gnomAD 17-39462142-C-T, REVEL 0.23, CADD 27.20
- S24S (p.Ser24Ser), gnomAD 17-39462143-A-G, CADD 13.70
- S25A (p.Ser25Ala), Ensembl rs2144848153, REVEL 0.17, CADD 23.70, Uncertain significance, not specified
- S25L (p.Ser25Leu), ExAC rs763482961, TOPMed rs763482961, gnomAD rs763482961, REVEL 0.21, CADD 28.10, Uncertain significance, not specified
- S25P (p.Ser25Pro), NCI-TCGA TCGA novel, REVEL 0.22, CADD 24.70, Variant assessed as somatic; moderate impact.
- S25W (p.Ser25Trp), ExAC rs763482961, TOPMed rs763482961, gnomAD rs763482961, REVEL 0.27, CADD 28.70, Uncertain significance
- S25S (p.Ser25Ser), rs764459801, gnomAD 17-39462146-G-C, CADD 12.90
- G26R (p.Gly26Arg), Ensembl rs2144848415
- G27V (p.Gly27Val), gnomAD 17-39462151-G-T, REVEL 0.20, CADD 27.30
- G27G (p.Gly27Gly), rs751971146, gnomAD 17-39462152-C-T, CADD 12.60
- G28D (p.Gly28Asp), TOPMed rs988490441, REVEL 0.28, CADD 27.90
- G28S (p.Gly28Ser), Ensembl rs2144848524, REVEL 0.20, CADD 24.30
- S29C (p.Ser29Cys), NCI-TCGA Cosmic COSV1014, cosmic curated COSV10142, Variant assessed as somatic; moderate impact.
- S29N (p.Ser29Asn), cosmic curated COSV71000, Ensembl rs2144848735
- S29R (p.Ser29Arg), Ensembl rs2144848794
- S30C (p.Ser30Cys), TOPMed rs1021399334, gnomAD rs1021399334, REVEL 0.16, CADD 26.00, Uncertain significance, not specified
- S30F (p.Ser30Phe), cosmic curated COSV71000, TOPMed rs1021399334, gnomAD rs1021399334, REVEL 0.16, CADD 26.50
- N31D (p.Asn31Asp), ExAC rs757500947, TOPMed rs757500947, gnomAD rs757500947, REVEL 0.12, CADD 24.70
- N31H (p.Asn31His), ExAC rs757500947, TOPMed rs757500947, gnomAD rs757500947
- N31K (p.Asn31Lys), ExAC rs781546834, TOPMed rs781546834, gnomAD rs781546834, REVEL 0.13, CADD 23.30, Likely benign
- N31S (p.Asn31Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- N31* (p.Asn31Ter), gnomAD 17-39462160-C-CT, CADD 26.60
- N31del (p.Asn31del), rs780413687, gnomAD 17-39462161-TAAC-, CADD 21.10
- N31N (p.Asn31Asn), rs781546834, gnomAD 17-39462164-C-T, CADD 13.00
- S32N (p.Ser32Asn), Ensembl rs2144849262
- S32R (p.Ser32Arg), TOPMed rs2049003045
- p.Ser32 His36del, rs1567667826, gnomAD 17-39462162-AACAG, CADD 21.70
- S32G (p.Ser32Gly), gnomAD 17-39462165-A-G, REVEL 0.18, CADD 27.20
- S32C (p.Ser32Cys), gnomAD 17-39462165-A-T, REVEL 0.26, CADD 28.60
- S32S (p.Ser32Ser), rs2049003045, gnomAD 17-39462167-C-T, CADD 14.90
- R33G (p.Arg33Gly), gnomAD rs1253774629, REVEL 0.28, CADD 24.70
- R33K (p.Arg33Lys), rs796501956, NCI-TCGA Cosmic COSV7100, cosmic curated COSV71002, REVEL 0.12, CADD 23.50, Variant assessed as somatic; moderate impact.
- R33T (p.Arg33Thr), gnomAD 17-39462169-G-C, REVEL 0.24, CADD 26.80
- E34G (p.Glu34Gly), gnomAD rs1252828858, REVEL 0.34, CADD 29.50, Uncertain significance, not specified
- R35C (p.Arg35Cys), ExAC rs750600272, TOPMed rs750600272, gnomAD rs750600272, REVEL 0.37, CADD 29.00, Uncertain significance, not specified
- R35H (p.Arg35His), Ensembl rs2144849716, REVEL 0.31, CADD 29.30
- R35R (p.Arg35Arg), rs2144849772, gnomAD 17-39462176-T-A, CADD 15.30
- H36L (p.His36Leu), gnomAD rs1181181380, REVEL 0.41, CADD 26.60
- H36N (p.His36Asn), Ensembl rs2144849869
- H36Q (p.His36Gln), TOPMed rs987591285, gnomAD rs987591285, REVEL 0.29, CADD 23.20, Uncertain significance, not specified
- H36D (p.His36Asp), gnomAD 17-39462177-C-G, REVEL 0.37, CADD 26.10
- R37C (p.Arg37Cys), TOPMed rs1406991934, gnomAD rs1406991934, REVEL 0.36, CADD 29.90, Uncertain significance, not specified
- R37G (p.Arg37Gly), TOPMed rs1406991934, gnomAD rs1406991934, REVEL 0.27, CADD 27.20, Uncertain significance, not specified
- R37H (p.Arg37His), NCI-TCGA Cosmic COSV1014, cosmic curated COSV10142, gnomAD rs1165442322, Variant assessed as somatic; moderate impact.
- R37P (p.Arg37Pro), gnomAD rs1165442322
- L38F (p.Leu38Phe), Ensembl rs2144850249, REVEL 0.11, CADD 26.30, Uncertain significance, not specified
- V39V (p.Val39Val), rs764318749, gnomAD 17-39462188-A-G, CADD 12.40
- S40L (p.Ser40Leu), ExAC rs780248349, TOPMed rs780248349, gnomAD rs780248349, REVEL 0.37, CADD 26.40, Uncertain significance, not specified
- S40T (p.Ser40Thr), Ensembl rs2144850383, REVEL 0.28, CADD 24.80
- S40W (p.Ser40Trp), ExAC rs780248349, TOPMed rs780248349, gnomAD rs780248349, REVEL 0.43, CADD 27.40, Uncertain significance, not specified
- S40S (p.Ser40Ser), gnomAD 17-39462191-G-C, CADD 14.40
- K41R (p.Lys41Arg), NCI-TCGA Cosmic COSV7099, Variant assessed as somatic; moderate impact.
- K41T (p.Lys41Thr), NCI-TCGA Cosmic COSV7099, cosmic curated COSV70999, Variant assessed as somatic; moderate impact.
- K41K (p.Lys41Lys), rs777513447, gnomAD 17-39462194-G-A, CADD 13.90
- H42Q (p.His42Gln), Ensembl rs2144850673
- H42Y (p.His42Tyr), Ensembl rs1181949082, REVEL 0.31, CADD 25.80, Uncertain significance, not specified
- K43E (p.Lys43Glu), ExAC rs746824859, gnomAD rs746824859, REVEL 0.41, CADD 29.20
- K43R (p.Lys43Arg), gnomAD 17-39462199-A-G, REVEL 0.33, CADD 24.80
- K43K (p.Lys43Lys), rs2049005394, gnomAD 17-39462200-G-A, CADD 13.20
- R44L (p.Arg44Leu), TOPMed rs1381858873, gnomAD rs1381858873, REVEL 0.57, CADD 32.00
- R44P (p.Arg44Pro), TOPMed rs1381858873, gnomAD rs1381858873
- R44W (p.Arg44Trp), gnomAD rs1286835635
- R44R (p.Arg44Arg), rs1286835635, gnomAD 17-39462201-C-A, CADD 13.90
- H45D (p.His45Asp), Ensembl rs964753901
- H45L (p.His45Leu), ExAC rs770625855, TOPMed rs770625855, gnomAD rs770625855, REVEL 0.49, CADD 27.50, Uncertain significance, not specified
- H45N (p.His45Asn), Ensembl rs964753901
- H45P (p.His45Pro), ExAC rs770625855, TOPMed rs770625855, gnomAD rs770625855, REVEL 0.35, CADD 27.60
- H45R (p.His45Arg), ExAC rs770625855, TOPMed rs770625855, gnomAD rs770625855, REVEL 0.27, CADD 24.40, Uncertain significance, not specified
- H45Y (p.His45Tyr), Ensembl rs964753901, REVEL 0.37, CADD 26.30
- K46M (p.Lys46Met), TOPMed rs1431923468, Uncertain significance, not specified
- K46N (p.Lys46Asn), Ensembl rs2144851416, Uncertain significance, not specified
- K46E (p.Lys46Glu), gnomAD 17-39462207-A-G, REVEL 0.40, CADD 28.80
- K46R (p.Lys46Arg), gnomAD 17-39462208-A-G, REVEL 0.19, CADD 23.80
- K46K (p.Lys46Lys), gnomAD 17-39462209-G-A, CADD 12.50
- S47C (p.Ser47Cys), TOPMed rs2049006693
- S47T (p.Ser47Thr), TOPMed rs2049006550
- S47Y (p.Ser47Tyr), TOPMed rs2049006693
- S47* (p.Ser47Ter), gnomAD 17-39462210-TCC-T, CADD 26.40
- K48R (p.Lys48Arg), 1000Genomes rs553421553, ExAC rs553421553, TOPMed rs553421553, gnomAD rs553421553, REVEL 0.12, CADD 23.20, Uncertain significance, not specified
- K48T (p.Lys48Thr), 1000Genomes rs553421553, ExAC rs553421553, TOPMed rs553421553, gnomAD rs553421553, REVEL 0.32, CADD 24.70, Uncertain significance
- K48P (p.Lys48Pro), gnomAD 17-39462207-A-AAG, CADD 29.30
- K48K (p.Lys48Lys), gnomAD 17-39462215-A-G, CADD 12.60
- H49D (p.His49Asp), Ensembl rs1597892218
- H49L (p.His49Leu), ExAC rs775003325, TOPMed rs775003325, gnomAD rs775003325, REVEL 0.45, CADD 26.70, Uncertain significance, not specified
- H49Q (p.His49Gln), 1000Genomes rs571927153, ExAC rs571927153, TOPMed rs571927153, gnomAD rs571927153, REVEL 0.33, CADD 23.60
- p.His49 Lys51del, rs751800128, gnomAD 17-39462209-GTCCA, CADD 20.60
- H49N (p.His49Asn), gnomAD 17-39462216-C-A, REVEL 0.34, CADD 25.00
- H49H (p.His49His), rs571927153, gnomAD 17-39462218-C-T, CADD 12.90
- S50A (p.Ser50Ala), Ensembl rs2049007757
- S50Y (p.Ser50Tyr), ExAC rs774720192, gnomAD rs774720192, REVEL 0.17, CADD 25.30, Uncertain significance, not specified
- S50C (p.Ser50Cys), gnomAD 17-39462220-C-G, REVEL 0.13, CADD 25.60
- S50F (p.Ser50Phe), gnomAD 17-39462220-C-T, REVEL 0.18, CADD 26.00
- K51E (p.Lys51Glu), TOPMed rs2049008179, gnomAD rs2049008179, REVEL 0.43, CADD 27.60, Uncertain significance, not specified
- K51I (p.Lys51Ile), Ensembl rs2144852257
- K51N (p.Lys51Asn), Ensembl rs2144852350
- K51R (p.Lys51Arg), cosmic curated COSV70999, Ensembl rs2144852257
- D52E (p.Asp52Glu), 1000Genomes rs542375286, ExAC rs542375286, gnomAD rs542375286
- D52H (p.Asp52His), Ensembl rs2144852446
- D52N (p.Asp52Asn), cosmic curated COSV10752, Ensembl rs2144852446
- D52V (p.Asp52Val), Ensembl rs2144852566
- D52Y (p.Asp52Tyr), Ensembl rs2144852446
- D52G (p.Asp52Gly), gnomAD 17-39462226-A-G, REVEL 0.28, CADD 28.00
- D52D (p.Asp52Asp), rs542375286, gnomAD 17-39462227-C-T, CADD 12.70
- M53I (p.Met53Ile), Ensembl rs2049008625
- M53L (p.Met53Leu), Ensembl rs754262105
- M53V (p.Met53Val), Ensembl rs754262105, REVEL 0.05, CADD 14.50, Uncertain significance, not specified
- M53T (p.Met53Thr), gnomAD 17-39462229-T-C, REVEL 0.06, CADD 15.30
- G54A (p.Gly54Ala), TOPMed rs1473672331, gnomAD rs1473672331, REVEL 0.18, CADD 22.80
- G54E (p.Gly54Glu), TOPMed rs1473672331, gnomAD rs1473672331, REVEL 0.22, CADD 24.50, Uncertain significance, not specified
- G54R (p.Gly54Arg), Ensembl rs2144852979, Uncertain significance, not specified
- G54V (p.Gly54Val), TOPMed rs1473672331, gnomAD rs1473672331, Uncertain significance, not specified
- G54W (p.Gly54Trp), Ensembl rs2144852979
- G54G (p.Gly54Gly), rs767753760, gnomAD 17-39462233-G-A, CADD 6.37
- L55F (p.Leu55Phe), Ensembl rs2144853449, cosmic curated COSV70999
- L55M (p.Leu55Met), TOPMed rs1413001100, gnomAD rs1413001100
Public CDK12 analysis runs
- CDK12 analysis run — CDK12 (3,156 variants) — completed 2026-08-19