PPM1A
protein-codingprotein phosphatase, Mg2+/Mn2+ dependent 1A, the group of Protein phosphatases, Mg2+/Mn2+ dependent
Gene summary
The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~53.3 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 PPM1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021003.5. 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 | 1 | 1 | ||||
| missense | 35 | 35 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 38 | 0 | 0 | 38 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066283.1 | 5 | MANE Select | |
| Ensembl | ENSP00000378514.4 | 5 | MANE Select | |
| RefSeq | NP_808820.1 | 2 | Standard | |
| RefSeq | NP_808821.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- MAPK signaling pathway - Homo sapiens (human)
- TGF-Ncore
- TGF-beta Signaling Pathway
- MAPK Signaling Pathway
- Signal Transduction
Biological Process
- negative regulation of transcription by RNA polymerase II
- protein dephosphorylation
- N-terminal protein myristoylation
- cell cycle arrest
- negative regulation of SMAD protein complex assembly
Molecular Function
- magnesium ion binding
- protein serine/threonine phosphatase activity
- magnesium-dependent protein serine/threonine phosphatase activity
- protein binding
- manganese ion binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000325642
- Coding exons
- 6
- Length
- 53336
- Individuals with no LoFs
- 124833
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 124834
- p
- 0.00000401
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.58 | 127 | 239 | 0.531 | 0.0000119 | 3023 |
| Missense (PolyPhen) | 6 | 81.403 | 0.073708 | 1011 | ||
| Synonymous | 0.418 | 80 | 84.9 | 0.942 | 0.00000448 | 816 |
| Loss of Function | 4.00 | 0 | 18.7 | 0.00 | 0.00000103 | 258 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling. Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB. {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:18930133}.;
Recessive Scores
- pRec
- 0.240
Intolerance Scores
- LoFtool
- 0.288
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 28.63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.990
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |