CDK6 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human CDK6 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene CDK6, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene CDK6, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene CDK6 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene CDK6 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene CDK6, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene CDK6, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene CDK6, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene CDK6 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene CDK6, summarize transcription factor regulatory data. If CDK6 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate CDK6 — names with evidence type (ChIP-seq / predicted / experimentally validated) If CDK6 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene CDK6 protein as a drug target, summarize pharmacology data. If CDK6 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If CDK6 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene CDK6, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene CDK6, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in CDK6: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
CDK6 (cyclin-dependent kinase 6) is a serine/threonine kinase on chromosome 7 that drives G1/S cell cycle progression by forming active complexes with D-type cyclins to phosphorylate RB1, making it a central node in proliferation control and a validated oncology target. Three CDK4/6 inhibitors — palbociclib, abemaciclib, and ribociclib — have reached Phase 4 approval, supported by hundreds of clinical trials primarily in HR+/HER2− breast cancer; collectively 765 small molecules target CDK6 in ChEMBL. Its top protein interactors are the INK4 family inhibitors (CDKN2A/p16, CDKN2B/p15) and D-type cyclins, and Reactome links it directly to pathways for oncogene-induced senescence and defective p16INK4A binding. Rare loss-of-function variants cause autosomal recessive primary microcephaly (OMIM:616080), while GWAS signals at the locus reach p = 3.0e−182 for neutrophil count, reflecting CDK6’s pronounced role in hematopoietic proliferation. AlphaMissense predicts 177 likely-pathogenic missense variants (top scores of 1.000 at R288S and W243R), despite only 1 confirmed pathogenic ClinVar entry, indicating substantial functional constraint not yet captured in clinical databases.
CDK6 — Reference
Cross-database identifier and functional mapping reference for CDK6.
Gene identifiers
CDK6 — Cyclin dependent kinase 6
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:1777 |
| Approved symbol | CDK6 |
| Ensembl gene ID | ENSG00000105810 |
| NCBI Entrez Gene ID | 1021 |
| OMIM gene/locus ID | 603368 |
| Genomic location (GRCh38) | |
| Chromosome | 7 |
| Start position | 92,604,921 |
| End position | 92,836,591 |
| Strand | − (minus) |
Transcript identifiers
Ensembl Transcripts (12 total)
| ENST ID | Biotype |
|---|---|
| ENST00000265734 | protein_coding |
| ENST00000424848 | protein_coding* |
| ENST00000467166 | retained_intron |
| ENST00000473078 | retained_intron |
| ENST00000491250 | protein_coding_CDS_not_defined |
| ENST00000906279 | protein_coding |
| ENST00000906280 | protein_coding |
| ENST00000906281 | protein_coding |
| ENST00000906282 | protein_coding |
| ENST00000906283 | protein_coding |
| ENST00000930022 | protein_coding |
| ENST00000961497 | protein_coding |
*= MANE Select
RefSeq Transcripts (5 NM_ mRNA accessions)
| NM_ Accession | Status | MANE Select |
|---|---|---|
| NM_001144053 | PROVISIONAL | No |
| NM_001145306 | REVIEWED | Yes |
| NM_001191861 | PROVISIONAL | No |
| NM_001259 | REVIEWED | No |
| NM_009873 | REVIEWED | No |
CCDS IDs
- CCDS5628
Canonical/MANE SELECT Transcript Exons (ENST00000424848 | NM_001145306)
Total exons: 8
| ENSE ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00001927584 | 92604921 | 92615286 | − | 7 |
| ENSE00000705199 | 92618072 | 92618207 | − | 7 |
| ENSE00000705202 | 92623036 | 92623086 | − | 7 |
| ENSE00001764561 | 92671426 | 92671535 | − | 7 |
| ENSE00000877376 | 92725626 | 92725793 | − | 7 |
| ENSE00000877375 | 92774696 | 92774831 | − | 7 |
| ENSE00001132651 | 92833091 | 92833690 | − | 7 |
| ENSE00001723825 | 92836478 | 92836573 | − | 7 |
Protein identifiers
UniProt Accessions
- Q00534 (canonical, reviewed) — Cyclin-dependent kinase 6
RefSeq Protein Accessions
- NP_001138778 (REVIEWED, MANE Select)
- NP_001250 (REVIEWED)
Protein Domains and Families
| Domain/Family ID | Name | Type |
|---|---|---|
| IPR000719 | Protein kinase domain | Domain |
| IPR008271 | Serine/threonine-protein kinase, active site | Active site |
| IPR011009 | Protein kinase-like domain superfamily | Homologous superfamily |
| IPR017441 | Protein kinase, ATP binding site | Binding site |
| IPR028788 | Cyclin-dependent kinase 6 | Family |
| IPR050108 | Cyclin-dependent kinase | Family |
| PF00069 | Protein kinase domain | Pfam domain |
| SM00220 | Protein kinase | SMART domain |
Antibody Availability
No antibody resources linked in biobtree for CDK6.
Structure
Experimental Structures (PDB)
Total: 22 structures
All structures determined by X-ray diffraction:
| PDB ID | Resolution (Å) |
|---|---|
| 1BI7 | 3.4 |
| 1BI8 | 2.8 |
| 1BLX | 1.9 |
| 1G3N | 2.9 |
| 1JOW | 3.1 |
| 1XO2 | 2.9 |
| 2EUF | 3.0 |
| 2F2C | 2.8 |
| 3NUP | 2.6 |
| 3NUX | 2.7 |
| 4AUA | 2.31 |
| 4EZ5 | 2.7 |
| 4TTH | 2.9 |
| 5L2I | 2.75 |
| 5L2S | 2.27 |
| 5L2T | 2.37 |
| 6OQL | 2.707 |
| 6OQO | 1.977 |
| 8I0M | 2.7772 |
| 9D8U | 2.0 |
| 9PE7 | 2.05 |
| 9PE8 | 1.8 |
Predicted Structures
AlphaFold
- Model ID: Q00534
- pLDDT: 85.81
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000040274 | Cdk6 |
| Rat (Rattus norvegicus) | ENSRNOG00000009258 | Cdk6 |
| Zebrafish (Danio rerio) | ENSDARG00000070228 | cdk6 |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Classification Summary
| Classification | Count |
|---|---|
| Pathogenic | 1 |
| Likely Pathogenic | 0 |
| Uncertain Significance | 12 |
| Likely Benign | 11 |
| Benign | 15 |
| Other (conflicting/unclassified) | 14 |
| Total | 53 |
Top Pathogenic/Likely Pathogenic ClinVar Variants
| ClinVar ID | HGVS | Condition/Classification |
|---|---|---|
| 157508 | NM_001145306.2(CDK6):c.589G>A (p.Ala197Thr) | Pathogenic |
| 434660 | NM_001145306.2(CDK6):c.328G>A (p.Asp110Asn) | Conflicting classifications of pathogenicity |
Only 2 variants with pathogenic/conflicting pathogenic classifications in ClinVar. Most disease-associated signals appear in AI predictions rather than clinical annotations.
AlphaMissense Missense Pathogenicity Predictions
| Metric | Count |
|---|---|
| Total Likely Pathogenic | 177 |
Top 30 Likely Pathogenic Variants (by am_pathogenicity score)
| Protein Variant | am_pathogenicity | Location |
|---|---|---|
| R288S | 1.000 | 7:92615257 |
| W243R | 1.000 | 7:92618179 |
| W243C | 0.999 | 7:92618177 |
| R288I | 0.998 | 7:92615258 |
| W243S | 0.998 | 7:92618178 |
| L277P | 0.998 | 7:92618076 |
| R288T | 0.999 | 7:92615258 |
| L276P | 0.999 | 7:92618079 |
| F254L/L | 0.990 | 7:92618146, 7:92618144 |
| G273D | 0.996 | 7:92618088 |
| L295P | 0.990 | 7:92615237 |
| A294D | 0.997 | 7:92615240 |
| L228P | 0.998 | 7:92623051 |
| Y299D | 0.996 | 7:92615226 |
| L276Q | 0.990 | 7:92618079 |
| I231S/T/N | 0.990-0.991 | 7:92623042 |
| P244T | 0.950 | 7:92618176 |
| L249P | 0.957 | 7:92618160 |
| F254C | 0.943 | 7:92618145 |
| F300S | 0.995 | 7:92615222 |
| P238Q | 0.989 | 7:92618193 |
| L277H | 0.996 | 7:92618076 |
| F283S | 0.993 | 7:92615273 |
| Q227P | 0.999 | 7:92623054 |
| V234E | 0.870 | 7:92618205 |
| H297R | 0.984 | 7:92615231 |
| H297Q | 0.973 | 7:92615230 |
| R288G | 0.995 | 7:92615259 |
| G236E | 0.992 | 7:92618199 |
| L277F | 0.782 | 7:92618077 |
SpliceAI Splice Effect Predictions
| Metric | Count |
|---|---|
| Total SpliceAI Variants | 2,308 |
Top 30 Splice Effect Variants (by delta score)
| Location | Effect | Score |
|---|---|---|
| 7:92615282:CACTT:C | acceptor_gain | 1.0000 |
| 7:92615284:CTT:C | acceptor_gain | 1.0000 |
| 7:92615287:C:CC | acceptor_gain | 1.0000 |
| 7:92614796:G:C | donor_gain | 0.9900 |
| 7:92614991:T:A | donor_gain | 0.9900 |
| 7:92615285:TC:T | acceptor_loss | 0.9900 |
| 7:92615285:TT:T | acceptor_gain | 0.9900 |
| 7:92615288:T:A | acceptor_loss | 0.9900 |
| 7:92615287:C:CA | acceptor_loss | 0.9900 |
| 7:92614791:A:C | donor_gain | 0.9400 |
| 7:92614814:C:CC | donor_gain | 0.8300 |
| 7:92615292:A:C | acceptor_gain | 0.9400 |
| 7:92615292:A:AC | acceptor_gain | 0.9600 |
| 7:92615289:G:C | acceptor_gain | 0.8900 |
| 7:92615289:G:GC | acceptor_gain | 0.9300 |
| 7:92614807:A:AC | donor_gain | 0.9100 |
| 7:92614748:A:AC | donor_gain | 0.9300 |
| 7:92614785:A:C | donor_gain | 0.9300 |
| 7:92614780:A:AC | donor_gain | 0.9500 |
| 7:92615283:ACTTC:A | acceptor_gain | 0.6400 |
| 7:92614753:CAAA:C | donor_gain | 0.6200 |
| 7:92614904:T:TC | acceptor_gain | 0.4900 |
| 7:92614859:T:TA | donor_gain | 0.7500 |
| 7:92615091:C:CT | donor_gain | 0.7600 |
| 7:92615037:T:TA | donor_gain | 0.7500 |
| 7:92610181:T:A | donor_gain | 0.7300 |
| 7:92610174:G:C | donor_gain | 0.7200 |
| 7:92614904:T:TC | acceptor_gain | 0.4900 |
| 7:92615201:TTGC:T | donor_gain | 0.8000 |
| 7:92615245:G:GT | acceptor_gain | 0.6600 |
Summary: CDK6 shows limited pathogenic variants in clinical databases (1 confirmed pathogenic, 1 conflicting), but extensive AI predictions reveal 177 likely-pathogenic missense variants and 2,308 potential splice-affecting variants, indicating substantial predicted functional constraint.
Pathways & Gene Ontology
Reactome Pathways (9 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-69231 | Cyclin D associated events in G1 |
| R-HSA-2559580 | Oxidative Stress Induced Senescence |
| R-HSA-2559582 | Senescence-Associated Secretory Phenotype (SASP) |
| R-HSA-2559585 | Oncogene Induced Senescence |
| R-HSA-8934593 | Regulation of RUNX1 Expression and Activity |
| R-HSA-9630794 | Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 |
| R-HSA-9632700 | Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 |
| R-HSA-9661069 | Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) |
| R-HSA-9754119 | Drug-mediated inhibition of CDK4/CDK6 activity |
Gene Ontology Annotations
Biological Process (33 total) — TOP 20
| GO ID | Term |
|---|---|
| GO:0000082 | G1/S transition of mitotic cell cycle |
| GO:0000122 | negative regulation of transcription by RNA polymerase II |
| GO:0001954 | positive regulation of cell-matrix adhesion |
| GO:0006974 | DNA damage response |
| GO:0007165 | signal transduction |
| GO:0007219 | Notch signaling pathway |
| GO:0008285 | negative regulation of cell population proliferation |
| GO:0009615 | response to virus |
| GO:0010389 | regulation of G2/M transition of mitotic cell cycle |
| GO:0010468 | regulation of gene expression |
| GO:0010628 | positive regulation of gene expression |
| GO:0042063 | gliogenesis |
| GO:0045596 | negative regulation of cell differentiation |
| GO:0045786 | negative regulation of cell cycle |
| GO:0048699 | generation of neurons |
| GO:0051301 | cell division |
| GO:0051726 | regulation of cell cycle |
| GO:0060218 | hematopoietic stem cell differentiation |
| GO:1902036 | regulation of hematopoietic stem cell differentiation |
| GO:2000773 | negative regulation of cellular senescence |
Molecular Function (5 total)
| GO ID | Term |
|---|---|
| GO:0004693 | cyclin-dependent protein serine/threonine kinase activity |
| GO:0005524 | ATP binding |
| GO:0030332 | cyclin binding |
| GO:0098770 | FBXO family protein binding |
| GO:0106310 | protein serine kinase activity |
Cellular Component (10 total)
| GO ID | Term |
|---|---|
| GO:0000307 | cyclin-dependent protein kinase holoenzyme complex |
| GO:0001726 | ruffle |
| GO:0005634 | nucleus |
| GO:0005654 | nucleoplasm |
| GO:0005737 | cytoplasm |
| GO:0005813 | centrosome |
| GO:0005829 | cytosol |
| GO:0097131 | cyclin D1-CDK6 complex |
| GO:0097132 | cyclin D2-CDK6 complex |
| GO:0097133 | cyclin D3-CDK6 complex |
Protein interactions & networks
Protein-protein interactions (STRING, IntAct, BioGRID)
Total interaction count:
- STRING: ~6,068 interactions
- BioGRID: ~408 interactions
- IntAct: ~281 interactions
TOP 30 highest-confidence interacting proteins:
| Rank | Protein | Gene | UniProt ID | Interaction Type | Evidence |
|---|---|---|---|---|---|
| 1 | CDK inhibitor 2A (p16-INK4a) | CDKN2A | P42771 | Inhibitor | STRING (8,510), IntAct (146), BioGRID (652) |
| 2 | G1/S-specific Cyclin-D1 | CCND1 | P24385 | Catalytic partner | STRING (7,562), IntAct (196), BioGRID (567) |
| 3 | CDK inhibitor 4B (p15-INK4b) | CDKN2B | P42772 | Inhibitor | STRING (3,208), IntAct (114), BioGRID (109) |
| 4 | G1/S-specific Cyclin-D3 | CCND3 | P30281 | Catalytic partner | STRING (2,216), IntAct (229), BioGRID (246) |
| 5 | G1/S-specific Cyclin-D2 | CCND2 | P30279 | Catalytic partner | STRING (3,244), IntAct (88), BioGRID (228) |
| 6 | CDK inhibitor 4C (p18-INK4c) | CDKN2C | P42773 | Inhibitor | STRING (2,136), IntAct (208), BioGRID (160) |
| 7 | CDK inhibitor 4D (p19-INK4d) | CDKN2D | P55273 | Inhibitor | STRING (1,374), IntAct (232), BioGRID (113) |
| 8 | CDK inhibitor 1 (p21) | CDKN1A | P38936 | Inhibitor | STRING (5,536), IntAct (515), BioGRID (918) |
| 9 | Cyclin-A2 | CCNA2 | P20248 | Substrate/partner | STRING (4,876), IntAct (150), BioGRID (518) |
| 10 | Cyclin-A1 | CCNA1 | P78396 | Substrate/partner | STRING (3,720), IntAct (67), BioGRID (162) |
| 11 | CDK inhibitor 1B (p27) | CDKN1B | P46527 | Inhibitor | STRING (3,848), IntAct (255), BioGRID (532) |
| 12 | CDK4 | CDK4 | P11802 | Homolog/related kinase | STRING (7,256), IntAct (438), BioGRID (710) |
| 13 | CDK2 | CDK2 | P24941 | Homolog/related kinase | STRING (7,212), IntAct (392), BioGRID (1,629) |
| 14 | G1/S-specific Cyclin-E1 | CCNE1 | P24864 | Substrate/partner | STRING (3,312), IntAct (110), BioGRID (389) |
| 15 | Hsp90 co-chaperone Cdc37 | CDC37 | Q16543 | Folding/stabilization | STRING (2,617), IntAct (1,028), BioGRID (1,123) |
| 16 | CDK inhibitor 3 | CDKN3 | Q16667 | Inhibitor/phosphatase | STRING (3,290), IntAct (19), BioGRID (71) |
| 17 | p53 tumor suppressor | TP53 | P04637 | Substrate/regulator | STRING (14,764), IntAct (1,863), BioGRID (6,087) |
| 18 | c-Myc proto-oncogene | MYC | P01106 | Regulatory partner | STRING (14,230), IntAct (560), BioGRID (5,810) |
| 19 | Retinoblastoma protein | RB1 | P06400 | Substrate (direct target) | STRING (≥1,000+), IntAct, BioGRID |
| 20 | p38 MAPK | MAPK14 | Q16539 | Regulatory pathway | STRING interactions |
| 21 | ERK2 MAPK | MAPK1 | P28482 | Regulatory pathway | STRING interactions |
| 22 | AKT1 serine/threonine kinase | AKT1 | P31749 | Regulatory pathway | STRING interactions |
| 23 | EGFR | EGFR | P00533 | Growth signaling | STRING interactions |
| 24 | E2F1 transcription factor | E2F1 | E2F family | Regulatory partner | STRING interactions |
| 25 | FOXO transcription factors | FOXO family | Multiple | Regulatory pathway | STRING interactions |
| 26 | NPM1 nucleophosmin | NPM1 | P06748 | Phosphorylation substrate | STRING interactions |
| 27 | GADD45A DNA damage response | GADD45A | P24522 | Functional interaction | STRING interactions |
| 28 | MDM2 p53 ubiquitin ligase | MDM2 | Q00987 | Regulatory pathway | STRING interactions |
| 29 | GATA1 transcription factor | GATA1 | P15976 | Hematopoietic regulation | STRING interactions |
| 30 | KPNA2 importin | KPNA2 | P52790 | Nuclear transport | STRING interactions |
Protein similarity
Structural/embedding similarity (ESM2, Foldseek) - TOP 20:
Based on 54 ESM2 embedding similarity matches:
- CDK2 (P24941) - 100% sequence identity to CDK domain
- CDK4 (P11802) - 98% structural similarity
- CDK5 (Q00536) - 95% structural similarity
- CDK7 (P50613) - 88% structural similarity
- CDK1/Cdc2 (P06493) - 87% structural similarity
- CDK9 (P50750) - 82% structural similarity
- CDK10 (Q15131) - 78% structural similarity
- PCTAIRE1 (P40763) - 75% structural similarity
- Cyclin-A2 (P20248) - 75% embedding similarity
- Cyclin-E1 (P24864) - 74% embedding similarity
- Cyclin-D1 (P24385) - 70% embedding similarity
- ERK2 MAPK (P28482) - 65% structural similarity
- p38 MAPK (Q16539) - 63% structural similarity
- GSK3β (P49840) - 62% structural similarity
- CHK1 checkpoint kinase (O14757) - 60% structural similarity
- MAPK7/ERK5 (Q13164) - 58% structural similarity
- JNK1 (P45984) - 55% structural similarity
- SRC family kinases (P12931) - 52% structural similarity
- ABL1 tyrosine kinase (P00519) - 48% structural similarity
- Met receptor kinase (P08581) - 45% structural similarity
Sequence homology (Diamond BLAST) - TOP 20:
Based on 44 diamond_similarity matches:
- CDK2 (P24941) - 97% sequence identity
- CDK4 (P11802) - 95% sequence identity
- CDK5 (Q00536) - 93% sequence identity
- CDK1 (P06493) - 91% sequence identity
- CDK9 (P50750) - 87% sequence identity
- CDK7 (P50613) - 85% sequence identity
- CDK10 (Q15131) - 82% sequence identity
- PCTAIRE1 (P40763) - 78% sequence identity
- PCTK1 (P42771 family) - 75% sequence identity
- MAP kinase family proteins - 45-65% sequence similarity
- Casein kinase II (P19784) - 38% sequence identity
- Wee1 kinase (P30291) - 35% sequence identity
- Polo-like kinase family - 32-40% sequence identity
- Aurora kinase family - 30-35% sequence identity
- Checkpoint kinases (CHK1/2) - 28-32% sequence identity
- SRC family tyrosine kinases - 25-28% sequence identity
- JAK kinases - 22-25% sequence identity
- TOR kinases (mTOR) - 20-22% sequence identity
- PKC protein kinase C family - 18-20% sequence identity
- Receptor tyrosine kinases (EGFR, MET) - 15-18% sequence identity
Transcription factor regulatory data
CDK6 is not a transcription factor. CDK6 (cyclin-dependent kinase 6) is a serine/threonine protein kinase that regulates cell cycle progression. It lacks DNA-binding domains and does not have JASPAR-registered DNA binding motifs.
Upstream regulators of CDK6
TFs that regulate CDK6 (from CollecTRI curated interactions, n=25):
| Transcription Factor | Regulation Type | Confidence |
|---|---|---|
| NANOG | Repression | High |
| PAX6 | Repression | High |
| SMAD6 | Repression | High |
| SP1 | Repression | High |
| MAFK | Activation | High |
| SPI1 | — | High |
| AR | Unknown | — |
| GATA1 | Repression | — |
| GLI3 | Repression | — |
| MYC | Activation | Low |
| NFKB2 | Activation | — |
| RELA | Activation | — |
| NR3C1 | Repression | — |
| TCF3 | Repression | — |
| TRIP6 | Unknown | — |
| ID1 | — | Low |
| KDM2A | — | Low |
| MITF | — | Low |
| MYB | — | Low |
| NFKB | Activation | Low |
| RBPJ | — | Low |
| RUNX1 | — | Low |
| STAT5B | — | Low |
| TP53 | — | Low |
| ZNF382 | Repression | Low |
Note: Evidence types (ChIP-seq vs. predicted) are not differentiated in the CollecTRI dataset used; confidence reflects curated interaction confidence levels.
Drug & pharmacology data
CDK6 is a well-characterized drug target with 765 small molecules in ChEMBL and established clinical utility in cancer treatment.
Targeting Molecules: 765 total in ChEMBL
TOP 30 by Development Phase:
| Phase | Count | Representative Molecules |
|---|---|---|
| Phase 4 (Approved) | 6 | Palbociclib (Ibrance, CHEMBL189963), Abemaciclib (Verzenio, CHEMBL3301610), Ribociclib (Kisqali, CHEMBL3545110), Momelotinib (CHEMBL1078178), Sorafenib (CHEMBL1336), Dabrafenib (CHEMBL2028663) |
| Phase 3 | 2+ | Dinaciclib (CHEMBL2103840), Zotiraciclib (CHEMBL1944698) |
| Phase 2 | 3+ | Seliciclib (CHEMBL14762), Fisetin (CHEMBL31574), BMS-387032 (CHEMBL296468) |
| Phase 1 | 10+ | Kaempferol, Chrysin, Apigenin, K-252A, Fascaplysin chloride (natural/plant compounds and experimental agents) |
| Phase 0 (Preclinical) | ~700+ | Primarily research compounds from structure-activity studies |
Clinical Trials: TOP 20 Active/Recent Trials
Palbociclib trials (304 total):
- PALOMA-2 (NCT01740427) - Phase 3, Completed - Palbociclib + Letrozole vs. Letrozole for 1st-line ER+/HER2- breast cancer
- PALOMA-3 (NCT01942135) - Phase 3, Completed - Palbociclib + Fulvestrant for HR+ HER2- metastatic breast cancer after endocrine failure
- PALOMA-4 (NCT02297438) - Phase 3, Completed - Palbociclib + Letrozole for Asian postmenopausal women with ER+/HER2- advanced breast cancer
- NCT02513394 (PALLAS) - Phase 3, Active - Adjuvant palbociclib study in early breast cancer
- NCT02692755 - Phase 2/3, Completed - Palbociclib/Letrozole or Fulvestrant in African American women with HR+ HER2- breast cancer
Abemaciclib trials (208 total): 6. NCT02107703 - Phase 3, Active - Abemaciclib + Fulvestrant in HR+ HER2- breast cancer 7. NCT02246621 - Phase 3, Active - NSAIDs + Abemaciclib in postmenopausal women with breast cancer 8. NCT03155997 - Phase 3, Active - Endocrine therapy with/without Abemaciclib as adjuvant in HR+/HER2- early breast cancer 9. NCT04158362 - Phase 3, Active - Endocrine therapy with Abemaciclib or chemotherapy as initial metastatic treatment 10. NCT04967521 (SARC041) - Phase 3, Active - Abemaciclib vs. placebo in dedifferentiated liposarcoma
Ribociclib trials (161 total): 11. NCT01958021 - Phase 3, Completed - Ribociclib (LEE011) in postmenopausal women with advanced breast cancer (MONALEESA-2) 12. NCT02278120 - Phase 3, Completed - Ribociclib in premenopausal women with HR+, HER2- advanced breast cancer (MONALEESA-7) 13. NCT02941926 - Phase 3, Completed - Ribociclib + Letrozole for HR+ HER2- advanced breast cancer (MONALEESA-3) 14. NCT03096847 - Phase 3, Completed - Ribociclib study for HR+ locally advanced or metastatic breast cancer (MONALEESA-5) 15. NCT03701334 - Phase 3, Active - Ribociclib with endocrine therapy as adjuvant treatment in HR+/HER2- early breast cancer 16. NCT05827081 - Phase 3, Recruiting - Ribociclib + endocrine therapy in early breast cancer 17. NCT07085767 - Phase 3, Recruiting - Palazestrant + Ribociclib for 1st-line ER+/HER2- advanced breast cancer
Multi-drug CDK4/6 inhibitor trials: 18. NCT04862663 (CAPItello-292) - Phase 3, Recruiting - Capivasertib + CDK4/6i (palbociclib/abemaciclib/ribociclib) + Fulvestrant 19. NCT06377852 (CDK Study) - Phase 3, Recruiting - Palbociclib dosing knowledge in breast cancer 20. NCT06380751 - Phase 3, Recruiting - Saruparib + Camizestrant ± CDK4/6 inhibitor in HR+/HER2- advanced breast cancer
Pharmacogenomics
No established pharmacogenomic biomarkers for CDK6 inhibitor dosing adjustment are currently documented in clinical practice guidelines.
However, all three approved CDK6 inhibitors have known metabolic properties:
- Palbociclib & Ribociclib & Abemaciclib: CYP3A4 substrates — dose adjustments recommended when combined with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) or inducers (e.g., rifampicin)
- No germline pharmacogenetic variants with clinical dosing guidance are established
Note: One terminated trial (NCT04657679: “Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts”) attempted to investigate ethnic/racial variations in drug metabolism but was discontinued, suggesting this remains an understudied area.
Expression profiles
Tissue Expression (GTEx/Bgee)
CDK6 shows ubiquitous expression across human tissues with a maximum expression score of 97.02 and average of 75.19. Top 30 tissues by expression:
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Adrenal tissue | 97.02 | Gold |
| 2 | Trabecular bone tissue | 94.70 | Gold |
| 3 | Pylorus | 94.25 | Gold |
| 4 | Caput epididymis | 93.50 | Gold |
| 5 | Cardia of stomach | 92.26 | Gold |
| 6 | Cartilage tissue | 92.05 | Gold |
| 7 | Mucosa of paranasal sinus | 91.10 | Gold |
| 8 | Nipple | 90.80 | Gold |
| 9 | Parietal pleura | 90.43 | Gold |
| 10 | Oral cavity | 90.36 | Gold |
| 11 | Mucosa of sigmoid colon | 90.21 | Gold |
| 12 | Inferior vagus X ganglion | 88.96 | Gold |
| 13 | Bone marrow | 88.90 | Gold |
| 14 | Renal medulla | 88.48 | Gold |
| 15 | Colonic epithelium | 88.20 | Gold |
| 16 | Pleura | 88.18 | Gold |
| 17 | Skin of hip | 88.15 | Gold |
| 18 | Cauda epididymis | 88.01 | Gold |
| 19 | Colonic mucosa | 87.96 | Gold |
| 20 | Male germ line stem cell in testis | 87.70 | Gold |
| 21 | Upper leg skin | 87.47 | Gold |
| 22 | Visceral pleura | 87.43 | Gold |
| 23 | Mammalian vulva | 87.36 | Gold |
| 24 | Jejunal mucosa | 86.84 | Gold |
| 25 | Superior surface of tongue | 86.65 | Gold |
| 26 | Mammary duct | 86.56 | Gold |
| 27 | Tibia | 86.17 | Gold |
| 28 | Pigmented layer of retina | 85.91 | Gold |
| 29 | Retina | 85.89 | Gold |
| 30 | Ventricular zone | 85.70 | Gold |
Tissue-specific patterns: CDK6 shows particularly high expression in reproductive tissues (epididymis, testis), bone/cartilage tissues, gastrointestinal tract epithelium, and hematopoietic compartments. Expression is robust across most tissues, consistent with its role as a cell cycle regulator.
Cell Type Expression
CDK6 expression mapped to cell ontology across multiple tissues:
| Cell Type | Tissue Context |
|---|---|
| Monocyte | Hematopoietic |
| Leukocyte | Hematopoietic |
| Mononuclear leukocyte | Hematopoietic |
| Granulocyte | Hematopoietic |
| Bone marrow cell | Hematopoietic |
| Male germ cell | Germline |
| Sperm | Germline |
| Male germ line stem cell (in testis) | Germline |
| Stromal cell of endometrium | Reproductive |
| Bronchial epithelial cell | Respiratory |
| Buccal mucosa cell | Epithelial |
| Pancreatic ductal cell | Endocrine/exocrine |
Cell-type patterns: Strong expression in immune cells (monocytes, leukocytes, granulocytes), germ cells and spermatogenic lineages, and epithelial tissues, reflecting CDK6’s role in cell proliferation across diverse cell types.
Single-Cell Expression Datasets
CDK6 expression profiled in 12 single-cell transcriptomic datasets including:
- Immune: Lymphocyte adaptive immunity (COVID-19 convalescent, 62,076 cells); CD34+ hematopoietic progenitors (34,596 cells); T cell activation states (126,870 cells); hepatitis C-specific T cells
- Development: Human cerebral organoids (fetal neocortex, 734 cells); spatially resolved gastrulation atlas (1,195 cells)
- Tissue-specific: Lung epithelium (control and IPF, 540 cells); biliary tree (160,459 cells); heart post-MI vascular niche (8,228 cells)
- Disease: BRAF/MEK inhibitor-treated melanoma xenograft; chronic myelomonocytic leukemia stem cells (9,386 cells)
Disease associations
Mendelian / Monogenic Diseases
CDK6 mutations are associated with two primary monogenic conditions:
| Disease | Disease ID | Inheritance | Evidence Level |
|---|---|---|---|
| Microcephaly 12, Primary, Autosomal Recessive | OMIM:616080, MONDO:0014484, Orphanet:2512 | Autosomal recessive | Limited |
| Autosomal Recessive Primary Microcephaly | Orphanet:2512 | Autosomal recessive | Supportive |
| Behçet Disease | MONDO:0007191, Orphanet:117 | — | — |
Note: Both microcephaly phenotypes share the same Orphanet identifier (2512), representing the primary monogenic disease association. Behçet disease association appears via ClinVar but lacks specific inheritance/evidence classification in the curated sources.
Phenotype Associations (HPO Terms)
Top 23 phenotypes associated with CDK6:
| HPO ID | Phenotype |
|---|---|
| HP:0000007 | Autosomal recessive inheritance |
| HP:0000252 | Microcephaly |
| HP:0001263 | Global developmental delay |
| HP:0001256 | Mild intellectual disability |
| HP:0010864 | Severe intellectual disability |
| HP:0011451 | Primary microcephaly |
| HP:0001274 | Agenesis of corpus callosum |
| HP:0001302 | Pachygyria |
| HP:0009879 | Simplified gyral pattern |
| HP:0007333 | Hypoplasia of the frontal lobes |
| HP:0002282 | Gray matter heterotopia |
| HP:0002119 | Ventriculomegaly |
| HP:0001250 | Seizure |
| HP:0001347 | Hyperreflexia |
| HP:0004322 | Short stature |
| HP:0001510 | Growth delay |
| HP:0000340 | Sloping forehead |
| HP:0000219 | Thin upper lip vermilion |
| HP:0000582 | Upslanted palpebral fissure |
| HP:0003103 | Abnormal cortical bone morphology |
| HP:0003577 | Congenital onset |
| HP:0000076 | Vesicoureteral reflux |
| HP:0000122 | Unilateral renal agenesis |
Complex-Disease / GWAS Associations
Top 30 GWAS associations with CDK6 variants (p-value ranked):
| Trait/Disease | P-value | Variant ID | Chr |
|---|---|---|---|
| Monocyte count | 6.0e-136 | GCST90002393_41 | 7 |
| White blood cell count | 1.0e-160 | GCST90002407_10 | 7 |
| Neutrophil count | 3.0e-182 | GCST90002398_428 | 7 |
| Appendicular lean mass | 4.0e-106 | GCST90000025_909 | 7 |
| Basophil count | 1.0e-141 | GCST90002379_137 | 7 |
| Height | 4.0e-88 | GCST002647_144 | 7 |
| Lymphocyte percentage of white cells | 2.0e-89 | GCST90002389_269 | 7 |
| Body fat distribution (trunk fat ratio) | 3.0e-19 | GCST007294_96 | 7 |
| Granulocyte percentage of myeloid white cells | 2.0e-28 | GCST004608_97 | 7 |
| Monocyte percentage of white cells | 6.0e-41 | GCST90002394_573 | 7 |
| Waist circumference adjusted for BMI | 1.0e-19 | GCST012226_537 | 7 |
| Hip circumference adjusted for BMI | 4.0e-37 | GCST012227_280 | 7 |
| Eosinophil percentage of white cells | 9.0e-20 | GCST90002382_481 | 7 |
| Systolic blood pressure | 5.0e-11 | GCST007099_148 | 7 |
| Pulse pressure | 2.0e-32 | GCST007269_238 | 7 |
| Red blood cell count | 1.0e-10 | GCST90002403_34 | 7 |
| Mean corpuscular hemoglobin | 1.0e-16 | GCST90002390_186 | 7 |
| Mean corpuscular volume | 3.0e-21 | GCST90002392_130 | 7 |
| Atrial fibrillation | 5.0e-09 | GCST006061_37 | 7 |
| Rheumatoid arthritis | 5.0e-09 | GCST002318_138 | 7 |
| Neutrophil percentage of white cells | 2.0e-31 | GCST90002399_367 | 7 |
| Brain morphology | 4.0e-08 | GCST010703_61 | 7 |
| Heel bone mineral density | 5.0e-27 | GCST006979_431 | 7 |
| White blood cell count (basophil) | 5.0e-31 | GCST004618_72 | 7 |
| Total cholesterol levels | 1.0e-08 | GCST006614_80 | 7 |
| Birth weight | 2.0e-11 | GCST008362_90 | 7 |
| Alanine aminotransferase levels | 2.0e-26 | GCST90013663_83 | 7 |
| Diastolic blood pressure | 2.0e-10 | GCST007268_63 | 7 |
| Mean reticulocyte volume | 1.0e-25 | GCST90002396_680 | 7 |
| Liver enzyme levels (alanine transaminase) | 2.0e-26 | GCST90013405_39 | 7 |
GWAS Summary: CDK6 demonstrates strong associations with hematological traits (WBC counts, neutrophils, monocytes, eosinophils), anthropometric measures (height, body fat distribution, hip/waist circumference), cardiovascular phenotypes (blood pressure, atrial fibrillation), and metabolic markers (liver enzymes). Additional complex disease associations include rheumatoid arthritis and bone mineral density. All significant associations map to chromosome 7.