PPM1D

Chr 17AD

protein phosphatase, Mg2+/Mn2+ dependent 1D

Also known as: IDDGIP, JDVS, PP2C-DELTA, WIP1

NCBI Gene: 8493UniProt: O15297

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. The expression of this gene is induced in a p53-dependent manner in response to various environmental stresses. While being induced by tumor suppressor protein TP53/p53, this phosphatase negatively regulates the activity of p38 MAP kinase, MAPK/p38, through which it reduces the phosphorylation of p53, and in turn suppresses p53-mediated transcription and apoptosis. This phosphatase thus mediates a feedback regulation of p38-p53 signaling that contributes to growth inhibition and the suppression of stress induced apoptosis. This gene is located in a chromosomal region known to be amplified in breast cancer. The amplification of this gene has been detected in both breast cancer cell line and primary breast tumors, which suggests a role of this gene in cancer development. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Breast cancer, somaticMIM #114480
Jansen-de Vries syndromeMIM #617450
AD
UniProtOvarian cancer
1
Active trials
419
ClinVar variants
87
Pathogenic / LP
2.7
Missense Z
1.10
LOEUF
10
Pubs (2 yr)
Clinical Summary— PPM1D
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
87 Pathogenic / Likely Pathogenic· 158 VUS of 419 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

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.
1.10LOEUF
pLI 0.000
Z-score 1.17
OE 0.75 (0.53–1.10)
Tolerant

Highly tolerant — LoF variants common in population

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.
2.70Z-score
OE missense 0.59 (0.52–0.66)
200 obs / 340.3 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.0.75 (0.53–1.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.52–0.66)
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.0.86
0≤1.21.6
LoF obs/exp: 20 / 26.5Missense obs/exp: 200 / 340.3Syn Z: 1.22

ClinVar Variant Classifications

419 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic41
VUS158
Likely Benign128
Benign27
Conflicting19
46
Pathogenic
41
Likely Pathogenic
158
VUS
128
Likely Benign
27
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
0
24
0
46
Likely Pathogenic
29
1
11
0
41
VUS
22
110
26
0
158
Likely Benign
0
34
28
66
128
Benign
0
7
17
3
27
Conflicting
—19
Total7315210669419

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

View in ClinVar →

Protein Context — Lollipop Plot

PPM1D · protein map & ClinVar variants

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

Gene2Phenotype Curations

PPM1D-related intellectual developmental disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Breast cancer, somatic

MIM #114480

Molecular basis of disorder known

Jansen-de Vries syndrome

MIM #617450

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
Bolton KL et al.·Nat Genet
2020
PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.
Hsu JI et al.·Cell Stem Cell
2018
Gain-of-function PPM1D mutations attenuate ischemic stroke.
He W et al.·Cell Death Differ
2025
Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.
Wojcik MH et al.·Am J Med Genet A
2023
Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescue and cancer mutations.
Gutierrez-Rodrigues F et al.·Blood
2024
Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease.
Gumuser ED et al.·J Am Coll Cardiol
2023Cohort
Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes.
Coombs CC et al.·Cell Stem Cell
2017Cohort
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.
Bonache S et al.·J Cancer Res Clin Oncol
2018
The role of the PPM1D gene in tumor pathogenesis.
Kucheryavenko AS et al.·Biomed Khim
2025Review
Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation.
Lindsley RC et al.·N Engl J Med
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias.
Badar T et al.·Blood Adv
2026Open AccessCohort
PPM1D is directly degraded by proteasomes in a ubiquitination-independent manner through its carboxyl-terminal region.
Takahashi M et al.·J Biomed Sci
2025Open Access
Association of high-dose radioactive iodine therapy with PPM1D-mutated clonal hematopoiesis in older individuals.
Kim J et al.·Mol Oncol
2025Open Access
Primary extraskeletal osteosarcoma of the esophagus with PPM1D-BCAS3 fusion: a case report and literature review.
Luo S et al.·Front Med (Lausanne)
2025Open AccessReview
Case Report: Novel truncating PPM1D variant in a dichorionic diamniotic (DCDA) twin with Jansen-de Vries syndrome. an updated perspective.
Merida De la Torre FJ et al.·Front Genet
2025Open AccessCase report
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
PPM1D activity promotes the replication stress caused by cyclin E1 overexpression
Martinikova AS et al.·Mol Oncol
2023
PPM1D in Solid and Hematologic Malignancies: Friend and Foe?
Zhang L et al.·Mol Cancer Res
2022
Discovery of a cryptic pocket in the AI-predicted structure of PPM1D phosphatase explains the binding site and potency of its allosteric inhibitors
Meller A et al.·Front Mol Biosci
2023
The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice
Yura Y et al.·Circ Res
2021
Discovery of a cryptic pocket in the AI-predicted structure of PPM1D phosphatase explains the binding site and potency of its allosteric inhibitors
Meller A et al.·bioRxiv
2023
PP2C phosphatases:terminators of suicidal thoughts
Lagorgette L et al.·Cell Death Dis
2024
PPM1D is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma
Yu Z et al.·Aging (Albany NY)
2021
PPM1D ameliorates Alzheimer's disease by promoting mitophagy.
Wang A et al.·Exp Neurol
2025
A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family
Biswas S et al.·Asian Pac J Cancer Prev
2023
Top 9 full-text resultsSearch PubTator3 ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Myelodysplastic SyndromeAcute Myeloid Leukemia

Evaluating Myelodysplastic Syndrome Risks in NET Patients Planned for Peptide Radionuclide Therapy

RECRUITING
NCT06510868University Health Network, TorontoStarted 2024-08-01
Peptide receptor radionuclide therapy (PRRT)Blood collection

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients