CDKN1A
protein-codingcyclin dependent kinase inhibitor 1A
Gene summary
This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]
- CDKN1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CDKN1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000389.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 10 | ||||
| missense | 23 | 3 | 1 | 27 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 27 | 13 | 1 | 42 |
Highest pathogenic variant AF is 0.0000049624714
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000380.1 | 2 | MANE Select | |
| Ensembl | ENSP00000244741.6 | 2 | MANE Select | |
| RefSeq | NP_001207706.1 | 2 | Standard | |
| RefSeq | NP_001207707.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cdkn1a | Danio rerio | Structure: regulation of mitotic cell cycle, embryonic Quality: disrupted abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Non-small cell lung cancer - Homo sapiens (human)
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
Biological Process
- regulation of cyclin-dependent protein serine/threonine kinase activity
- G1/S transition of mitotic cell cycle
- G2/M transition of mitotic cell cycle
- regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase II promoter
Molecular Function
- cyclin-dependent protein serine/threonine kinase activity
- protein kinase inhibitor activity
- cyclin-dependent protein serine/threonine kinase inhibitor activity
- protein binding
- protein kinase binding
Cellular Component
- cyclin-dependent protein kinase holoenzyme complex
- nucleus
- nucleoplasm
- nucleolus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000405375
- Coding exons
- 2
- Length
- 10812
- Individuals with no LoFs
- 125721
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125731
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.416 | 104 | 117 | 0.892 | 0.00000865 | 1024 |
| Missense (PolyPhen) | 35 | 39.55 | 0.88494 | 348 | ||
| Synonymous | 0.642 | 40 | 45.5 | 0.879 | 0.00000290 | 371 |
| Loss of Function | 0.871 | 5 | 7.59 | 0.659 | 5.61e-7 | 61 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739). {ECO:0000269|PubMed:11595739, ECO:0000269|PubMed:8242751, ECO:0000269|PubMed:9106657}.;
Recessive Scores
- pRec
- 0.0908
Intolerance Scores
- LoFtool
- 0.232
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.46
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.995
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |