CDK6

Chr 7AR

cyclin dependent kinase 6

Also known as: MCPH12, PLSTIRE

NCBI Gene: 1021ENSG00000105810UniProt: Q00534

The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. Altered expression of this gene has been observed in multiple human cancers. A mutation in this gene resulting in reduced cell proliferation, and impaired cell motility and polarity, and has been identified in patients with primary microcephaly. [provided by RefSeq, Aug 2017]

Primary Disease Associations & Inheritance

?Microcephaly 12, primary, autosomal recessiveMIM #616080
AR
57
ClinVar variants
15
Pathogenic / LP
0.98
pLI score· haploinsufficient
8
Active trials
Clinical Summary— CDK6
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 15 VUS of 57 total submissions
💊
Clinical Trials
8 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.
0.28LOEUF
pLI 0.983
Z-score 3.58
OE 0.06 (0.02–0.28)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.06Z-score
OE missense 0.37 (0.31–0.45)
70 obs / 188.1 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.0.06 (0.02–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.37 (0.31–0.45)
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.0.92
0≤1.21.6
LoF obs/exp: 1 / 16.8Missense obs/exp: 70 / 188.1Syn Z: 0.54

ClinVar Variant Classifications

57 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
VUS15
Likely Benign12
Benign14
Conflicting1
15
Pathogenic
15
VUS
12
Likely Benign
14
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
14
0
15
Likely Pathogenic
0
0
0
0
0
VUS
0
12
3
0
15
Likely Benign
0
1
1
10
12
Benign
0
0
12
2
14
Conflicting
—1
Total014301257

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

View in ClinVar →

Protein Context — Lollipop Plot

CDK6 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Microcephaly 12, primary, autosomal recessive

MIM #616080

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CDK6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
Dilly J et al.·Cancer Discov
2024Functional
CDK4 and CDK6 kinases: From basic science to cancer therapy.
Fassl A et al.·Science
2022Review
Targeting CDK4 and CDK6 in cancer.
Goel S et al.·Nat Rev Cancer
2022Review
Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.
Turner NC et al.·N Engl J Med
2015Clinical trial
CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety.
Palmer CL et al.·Cancer Cell
2025
The history and future of targeting cyclin-dependent kinases in cancer therapy.
Asghar U et al.·Nat Rev Drug Discov
2015Review
Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer.
Goodwin CM et al.·Cancer Res
2023Clinical trial
Whole genomes redefine the mutational landscape of pancreatic cancer.
Waddell N et al.·Nature
2015
Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.
Glaviano A et al.·Drug Resist Updat
2024Review
Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.
Freeman-Cook K et al.·Cancer Cell
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Advanced LymphomaAdvanced Malignant Solid NeoplasmRefractory Lymphoma

Testing Palbociclib (PD-0332991) as Potentially Targeting Treatment in Cancers With CDK4 or CDK6 Amplification (MATCH - Subprotocol Z1C)

ACTIVE NOT RECRUITING
NCT06390839Phase PHASE2National Cancer Institute (NCI)Started 2017-03-22
Biopsy ProcedureBiospecimen CollectionComputed Tomography
Cancer

Study of the CDK4/6 Inhibitor Abemaciclib in Solid Tumors Harboring Genetic Alterations in Genes Encoding D-Type Cyclins or Amplification of CDK4 or CDK6

RECRUITING
NCT03310879Phase PHASE2Dana-Farber Cancer InstituteStarted 2017-11-21
Abemaciclib
CDK4/6 InhibitorBreast CancerCYP3A4 Protein, Human

Pharmacogenomic and Circulating Biomarkers for CDK4/6 Inhibitors

ENROLLING BY INVITATION
NCT07100054London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sStarted 2025-10-10
Whole gene sequencingDrug-drug interaction analysisBiomarker analysis
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
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
Anatomic Stage IV Breast Cancer AJCC v8Metastatic HER2-Negative Breast CarcinomaMetastatic Hormone Receptor-Positive Breast Carcinoma

A Vaccine (STEMVAC) With Standard Endocrine-Based Therapy or Chemotherapy for the Treatment of Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

RECRUITING
NCT07112053Phase PHASE2University of WashingtonStarted 2025-11-17
CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope Plasmid DNA VaccineCapecitabineComputed Tomography
NSCLC

A Study With BPI-1178 and Osimertinib in Advanced Non-small Cell Lung Cancer Patients With EGFR Mutations

RECRUITING
NCT06362980Phase PHASE1National Cancer Center, ChinaStarted 2024-05-22
BPI-1178Osimertinib
Breast Neoplasms

Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.

ACTIVE NOT RECRUITING
NCT03283384Phase PHASE2Borstkanker Onderzoek GroepStarted 2019-06-15
LetrozoleChemotherapyRibociclib plus letrozole

External Resources

Links to major genomics databases and tools