CDKN2A
Chr 9ADcyclin dependent kinase inhibitor 2A
Also known as: ARF, CAI2, CDK4I, CDKN2, CMM2, INK4, INK4A, MLM
This gene encodes multiple protein isoforms including CDK4/CDK6 inhibitors that regulate cell cycle progression and an ARF protein that stabilizes the tumor suppressor p53. Germline mutations cause autosomal dominant familial cancer syndromes including melanoma-pancreatic cancer syndrome and melanoma with neural system tumors. The gene has relatively low constraint scores, consistent with its role in cancer predisposition rather than severe developmental disorders.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 30 | 1 | 18 | 0 | 49 |
Likely Pathogenic | 12 | 5 | 3 | 0 | 20 |
VUS | 12 | 177 | 31 | 3 | 223 |
Likely Benign | 2 | 21 | 49 | 76 | 148 |
Benign | 0 | 0 | 27 | 5 | 32 |
Conflicting | — | 14 | |||
| Total | 56 | 204 | 128 | 84 | 486 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in 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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Prospective Registry for Patients at High-Risk for Pancreatic Cancer
RECRUITINGCanadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGctDNA Assay in Patients With Resectable Pancreatic Cancer
RECRUITINGRegression of Cervical Precancerous Lesions and Associated Risk Factors
RECRUITINGA Pancreatic Cancer Screening Study in Hereditary High Risk Individuals
RECRUITINGLong-Term Follow-Up in Women With Early Breast Cancer Three Years of More Post Primary Treatment
ACTIVE NOT RECRUITINGAn 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
RECRUITINGMoving Foward With Myeloma (MFM)
NOT YET RECRUITINGEvaluation of the Efficacy of Calcium a -Ketoglutarate(AKG-Ca) in Improving Human Aging
ACTIVE NOT RECRUITINGPancreatic Cancer Early Detection Consortium
RECRUITINGA Phase II Study of Anti-EGFR Antibody-drug Conjugate (ADC) Combine With CDK4/6 Inhibitors Posterior Line in the Treatment of Recurrent/Metastatic CDKN2A Gene Variant Head and Neck Squamous Cell Carcinoma
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools