CDKN2A

Chr 9AD

cyclin dependent kinase inhibitor 2A

Also known as: ARF, CAI2, CDK4I, CDKN2, CMM2, INK4, INK4A, MLM

NCBI Gene: 1029ENSG00000147889UniProt: P42771

This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

Primary Disease Associations & Inheritance

{Melanoma and neural system tumor syndrome}MIM #155755
AD
{Melanoma-pancreatic cancer syndrome}MIM #606719
AD
{Melanoma, cutaneous malignant, 2}MIM #155601
AD
UniProtFamilial atypical multiple mole melanoma-pancreatic carcinoma syndrome
UniProtMelanoma-astrocytoma syndrome
0
ClinVar variants
0
Pathogenic / LP
0.39
pLI score
12
Active trials
Clinical Summary— CDKN2A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.95LOEUF
pLI 0.395
Z-score 1.65
OE 0.20 (0.07–0.95)
Tolerant

Typical tolerance to LoF variation

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.
-1.01Z-score
OE missense 1.28 (1.11–1.47)
136 obs / 106.6 exp
Tolerant

Tolerant to missense variation

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.0.20 (0.07–0.95)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.28 (1.11–1.47)
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.1.09
0≤1.21.6
LoF obs/exp: 1 / 5.0Missense obs/exp: 136 / 106.6Syn Z: -0.51

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

CDKN2A · protein map & ClinVar variants

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

Gene2Phenotype Curations

CDKN2A-related melanoma, cutaneous malignant

definitive
ADLoss Of FunctionAbsent Gene Product
SkinCancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Melanoma and neural system tumor syndrome}

MIM #155755

Molecular basis of disorder known

Autosomal dominant

{Melanoma-pancreatic cancer syndrome}

MIM #606719

Molecular basis of disorder known

Autosomal dominant

{Melanoma, cutaneous malignant, 2}

MIM #155601

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis.
Minami JK et al.·Cancer Cell
2023Functional
Unmasking Transcriptional Heterogeneity in Senescent Cells.
Hernandez-Segura A et al.·Curr Biol
2017
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.
Mirabello L et al.·JAMA Oncol
2020Cohort
T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness.
Bardelli V et al.·Genes (Basel)
2021Review
Integrative clinical genomics of metastatic cancer.
Robinson DR et al.·Nature
2017
Proliferative Leukoplakia.
Al-Hadlaq M et al.·Dent Clin North Am
2025Review
Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.
Breunig M et al.·Cell Stem Cell
2021Functional
Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients.
Yin X et al.·Nat Commun
2025Cohort
Hereditary pancreatic cancer.
Abe K et al.·Int J Clin Oncol
2021Review
Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.
Tang Q et al.·Autophagy
2025
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
BRCA1 MutationPOLD1 Gene MutationCDKN2A Mutation

An Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk and An Intervention to Help Patients and Their Primary Care Providers Stay Up-to-date About Uncertain Genetic Test Results

RECRUITING
NCT05420064Phase NAMemorial Sloan Kettering Cancer CenterStarted 2022-12-01
Intervention Arm At-risk Relative/ARR ContactsMyGene PortalStandard of Care
Pancreas Cancer

ctDNA Assay in Patients With Resectable Pancreatic Cancer

RECRUITING
NCT05052671University of OklahomaStarted 2022-05-25
Gastric CancerHealthy

Preliminary Experimental Study on Key Technologies for Early Screening of Gastric Cancer

RECRUITING
NCT05991947Zhejiang Cancer HospitalStarted 2021-03-01
No intervention
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
Pancreas CancerExosomesExtracellular Vesicles

ExoLuminate Study for Early Detection of Pancreatic Cancer

RECRUITING
NCT05625529Biological DynamicsStarted 2022-12-19
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
Hereditary Pancreatic Cancer

The PREPAIRD Study: Personalized Surveillance for Early Detection of Pancreatic Cancer in High Risk Individuals

ENROLLING BY INVITATION
NCT05740111Phase NAOslo University HospitalStarted 2022-09-01
Annual surveillance
RhA - Rheumatoid Arthritis

Adversity and Its Association With the Development and Expression of Rheumatic Diseases

NOT YET RECRUITING
NCT06386380National Institute of Medical Sciences and Nutrition, Salvador ZubiranStarted 2024-06-01
Rheumatic diseases Mistreatment Scale (RDMS)Routine assessment of patient index data 3 (RAPID-3)Health Assessment Questionnaire (HAQ)
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Uroepithelial Carcinoma

Current Status of Diagnosis and Treatment of Uroepithelial Carcinoma

NOT YET RECRUITING
NCT06663735The First Affiliated Hospital of Xinxiang Medical CollegeStarted 2024-10-30
Pancreatic CancerPancreatic Ductal AdenocarcinomaPDAC

A Prospective Registry for Patients at High-Risk for Pancreatic Cancer

RECRUITING
NCT06151223Mayo ClinicStarted 2021-07-13
Bio-specimen Collection: BloodBio-specimen Collection: Pancreatic JuiceMRI
PIK3CA MutationSolid Tumor, AdultHER2-negative Breast Cancer

First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer

RECRUITING
NCT05216432Phase PHASE1Relay Therapeutics, Inc.Started 2021-12-08
RLY-2608FulvestrantPalbociclib 125mg

External Resources

Links to major genomics databases and tools