PPM1D (Protein phosphatase 1D) variants and mutations
PPM1D (also known as Protein phosphatase 1D) is a human protein-coding gene encoding a protein phosphatase 1D protein. It turns off DNA-damage signaling by dephosphorylating p53-pathway and checkpoint proteins after cellular stress. Truncating mutations that stabilize the protein occur in clonal hematopoiesis and cancer and can confer a selective advantage after genotoxic therapy. This analysis covers 1,302 PPM1D variants and mutations. Of these, 68% have computational variant effect predictions. Disease context includes intellectual developmental disorder with gastrointestinal difficulties and high, hereditary disease, and neurodegenerative disease. Example PPM1D variants include A2T, A2P, and A2S.
Variant analysis overview
- Gene: PPM1D
- Protein: Protein phosphatase 1D
- UniProt accession: O15297
- Organism: Homo sapiens
- Variants analyzed: 1302
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 879 unspecified-consequence records; 244 missense variants; 143 synonymous variants; 17 stop-gained variants; 11 frameshift variants; 5 in-frame deletions; 1 in-frame insertions; 1 splice-region variants; 1 substitution
- Prediction scores: 883 variants have prediction scores (68% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: intellectual developmental disorder with gastrointestinal difficulties and high, hereditary disease, neurodegenerative disease, hereditary breast carcinoma, Hereditary breast cancer, ovarian carcinoma, malignant glioma, syndromic intellectual disability, colorectal adenocarcinoma, essential thrombocythemia, pilocytic astrocytoma, breast ductal adenocarcinoma.
Protein structure and variant hotspots
- Protein features: 1 domains; 5 binding sites; 2 post-translational modification sites.
- Structural context: 773 variants have structural context.
- PTM context: 6 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable PPM1D variants
Examples include A2T, A2P, A2S, A2E, A2V, A2A, G3R, G3E. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2T (p.Ala2Thr), gnomAD 17-60600418-G-A, REVEL 0.07, MetaLR 0.11
- A2P (p.Ala2Pro), gnomAD 17-60600418-G-C, REVEL 0.17, MetaLR 0.17
- A2S (p.Ala2Ser), gnomAD 17-60600418-G-T, REVEL 0.11, MetaLR 0.09
- A2E (p.Ala2Glu), gnomAD 17-60600419-C-A, REVEL 0.09, MetaLR 0.05
- A2V (p.Ala2Val), gnomAD 17-60600419-C-T, REVEL 0.08, MetaLR 0.08
- A2A (p.Ala2Ala), gnomAD 17-60600420-G-T, CADD 15.60
- G3R (p.Gly3Arg), cosmic curated COSV59955, Ensembl rs2030178445
- G3E (p.Gly3Glu), gnomAD 17-60600422-G-A, REVEL 0.07, MetaLR 0.17
- G3V (p.Gly3Val), gnomAD 17-60600422-G-T, REVEL 0.12, MetaLR 0.19
- G3G (p.Gly3Gly), gnomAD 17-60600423-G-T, CADD 15.20
- L4M (p.Leu4Met), gnomAD 17-60600424-C-A, REVEL 0.07, MetaLR 0.03
- L4P (p.Leu4Pro), gnomAD 17-60600425-T-C, REVEL 0.18, MetaLR 0.01
- L4L (p.Leu4Leu), rs1170080371, gnomAD 17-60600426-G-A, CADD 14.40
- Y5C (p.Tyr5Cys), gnomAD 17-60600428-A-G, REVEL 0.15, MetaLR 0.05
- Y5Y (p.Tyr5Tyr), gnomAD 17-60600429-C-T, CADD 13.80
- Y5* (p.Tyr5Ter), gnomAD 17-60600429-C-A, CADD 37.00
- S6L (p.Ser6Leu), gnomAD 17-60600431-C-T, REVEL 0.05, MetaLR 0.03
- S6* (p.Ser6Ter), gnomAD 17-60600431-C-A, CADD 37.00
- S6S (p.Ser6Ser), gnomAD 17-60600432-G-C, CADD 13.20
- L7M (p.Leu7Met), gnomAD 17-60600433-C-A, REVEL 0.10, MetaLR 0.06
- L7L (p.Leu7Leu), rs1598396550, gnomAD 17-60600433-C-T, CADD 14.70
- L7P (p.Leu7Pro), gnomAD 17-60600434-T-C, REVEL 0.18, MetaLR 0.06
- G8A (p.Gly8Ala), gnomAD rs1415006641, REVEL 0.10, CADD 20.00
- G8E (p.Gly8Glu), gnomAD 17-60600437-G-A, REVEL 0.14, MetaLR 0.04
- G8G (p.Gly8Gly), gnomAD 17-60600438-A-G, CADD 16.80
- V9M (p.Val9Met), gnomAD 17-60600439-G-A, REVEL 0.09, MetaLR 0.03
- V9E (p.Val9Glu), gnomAD 17-60600440-T-A, REVEL 0.24, MetaLR 0.07
- V9A (p.Val9Ala), gnomAD 17-60600440-T-C, REVEL 0.13, MetaLR 0.03
- V9V (p.Val9Val), gnomAD 17-60600441-G-A, CADD 14.80
- S10R (p.Ser10Arg), Ensembl rs867538058, REVEL 0.26, CADD 27.10
- S10G (p.Ser10Gly), gnomAD 17-60600442-A-G, REVEL 0.31, MetaLR 0.06
- S10N (p.Ser10Asn), gnomAD 17-60600443-G-A, REVEL 0.21, MetaLR 0.08
- S10I (p.Ser10Ile), gnomAD 17-60600443-G-T, REVEL 0.39, MetaLR 0.08
- S10S (p.Ser10Ser), gnomAD 17-60600444-C-T, CADD 15.80
- V11A (p.Val11Ala), TOPMed rs1476949755, gnomAD rs1476949755, REVEL 0.07, CADD 23.10
- V11F (p.Val11Phe), gnomAD 17-60600445-G-T, REVEL 0.08, MetaLR 0.03
- V11I (p.Val11Ile), gnomAD 17-60600445-G-A, REVEL 0.08, MetaLR 0.02
- V11D (p.Val11Asp), gnomAD 17-60600446-T-A, REVEL 0.14, MetaLR 0.06
- V11V (p.Val11Val), rs1379005491, gnomAD 17-60600447-C-T, CADD 14.30
- F12S (p.Phe12Ser), gnomAD 17-60600449-T-C, REVEL 0.12, MetaLR 0.01
- F12L (p.Phe12Leu), gnomAD 17-60600450-C-A, REVEL 0.12, MetaLR 0.02
- F12F (p.Phe12Phe), gnomAD 17-60600450-C-T, CADD 15.60
- S13P (p.Ser13Pro), gnomAD 17-60600451-T-C, REVEL 0.15, MetaLR 0.08
- S13Y (p.Ser13Tyr), gnomAD 17-60600452-C-A, REVEL 0.11, MetaLR 0.03
- S13S (p.Ser13Ser), gnomAD 17-60600453-C-T, CADD 6.64
- D14E (p.Asp14Glu), Ensembl rs1199709240, REVEL 0.06, CADD 21.60
- D14N (p.Asp14Asn), gnomAD 17-60600454-G-A, REVEL 0.20, MetaLR 0.06
- D14Y (p.Asp14Tyr), gnomAD 17-60600454-G-T, REVEL 0.36, MetaLR 0.08
- D14V (p.Asp14Val), gnomAD 17-60600455-A-T, REVEL 0.31, MetaLR 0.07
- D14G (p.Asp14Gly), gnomAD 17-60600455-A-G, REVEL 0.30, MetaLR 0.07
- D14D (p.Asp14Asp), gnomAD 17-60600456-C-T, CADD 14.70
- Q15H (p.Gln15His), Ensembl rs866229886, REVEL 0.23, CADD 27.90
- Q15R (p.Gln15Arg), gnomAD rs1178110228, REVEL 0.27, CADD 28.40
- Q15K (p.Gln15Lys), gnomAD 17-60600457-C-A, REVEL 0.27, MetaLR 0.08
- Q15* (p.Gln15Ter), gnomAD 17-60600457-C-T, CADD 38.00
- G16C (p.Gly16Cys), gnomAD 17-60600460-G-T, REVEL 0.53, MetaLR 0.13
- G16V (p.Gly16Val), gnomAD 17-60600461-G-T, REVEL 0.40, MetaLR 0.12
- G16D (p.Gly16Asp), gnomAD 17-60600461-G-A, REVEL 0.39, MetaLR 0.12
- G16G (p.Gly16Gly), gnomAD 17-60600462-C-A, CADD 15.00
- G17W (p.Gly17Trp), NCI-TCGA TCGA novel, REVEL 0.46, CADD 32.00, Variant assessed as somatic; moderate impact.
- G17R (p.Gly17Arg), gnomAD 17-60600463-G-A, REVEL 0.39, MetaLR 0.07
- G17V (p.Gly17Val), gnomAD 17-60600464-G-T, REVEL 0.34, MetaLR 0.06
- G17E (p.Gly17Glu), gnomAD 17-60600464-G-A, REVEL 0.34, MetaLR 0.07
- G17G (p.Gly17Gly), rs1357305560, gnomAD 17-60600465-G-A, CADD 15.70
- R18G (p.Arg18Gly), gnomAD 17-60600462-CG-C, CADD 32.00
- R18K (p.Arg18Lys), gnomAD 17-60600467-G-A, REVEL 0.34, MetaLR 0.11
- R18M (p.Arg18Met), gnomAD 17-60600467-G-T, REVEL 0.46, MetaLR 0.11
- R18R (p.Arg18Arg), gnomAD 17-60600468-G-A, CADD 16.00
- R18S (p.Arg18Ser), gnomAD 17-60600468-G-T, REVEL 0.28, MetaLR 0.10
- K19E (p.Lys19Glu), ExAC rs759976092, gnomAD rs759976092, REVEL 0.27, CADD 32.00
- K19T (p.Lys19Thr), gnomAD 17-60600470-A-C, REVEL 0.30, MetaLR 0.07
- K19R (p.Lys19Arg), gnomAD 17-60600470-A-G, REVEL 0.17, MetaLR 0.07
- K19M (p.Lys19Met), gnomAD 17-60600470-A-T, REVEL 0.35, MetaLR 0.07
- K19K (p.Lys19Lys), rs1298510693, gnomAD 17-60600471-G-A, CADD 15.10
- K19N (p.Lys19Asn), gnomAD 17-60600471-G-T, REVEL 0.17, MetaLR 0.08
- Y20N (p.Tyr20Asn), gnomAD 17-60600472-T-A, REVEL 0.44, MetaLR 0.07
- Y20C (p.Tyr20Cys), gnomAD 17-60600473-A-G, REVEL 0.55, MetaLR 0.07
- Y20F (p.Tyr20Phe), gnomAD 17-60600473-A-T, REVEL 0.31, MetaLR 0.07
- Y20Y (p.Tyr20Tyr), gnomAD 17-60600474-C-T, CADD 14.00
- Y20* (p.Tyr20Ter), gnomAD 17-60600474-C-A, CADD 37.00
- M21L (p.Met21Leu), gnomAD 17-60600475-A-T, REVEL 0.28, MetaLR 0.07
- M21V (p.Met21Val), gnomAD 17-60600475-A-G, REVEL 0.33, MetaLR 0.07
- M21T (p.Met21Thr), gnomAD 17-60600476-T-C, REVEL 0.38, MetaLR 0.07
- M21I (p.Met21Ile), gnomAD 17-60600477-G-T, REVEL 0.29, MetaLR 0.08
- E22* (p.Glu22Ter), gnomAD 17-60600478-G-T, CADD 39.00
- E22K (p.Glu22Lys), gnomAD 17-60600478-G-A, REVEL 0.34, MetaLR 0.11
- E22V (p.Glu22Val), gnomAD 17-60600479-A-T, REVEL 0.44, MetaLR 0.12
- E22G (p.Glu22Gly), gnomAD 17-60600479-A-G, REVEL 0.44, MetaLR 0.12
- E22D (p.Glu22Asp), gnomAD 17-60600480-G-T, REVEL 0.15, MetaLR 0.10
- E22E (p.Glu22Glu), rs768053644, gnomAD 17-60600480-G-A, CADD 14.70
- D23Y (p.Asp23Tyr), gnomAD 17-60600481-G-T, REVEL 0.55, MetaLR 0.25
- D23D (p.Asp23Asp), gnomAD 17-60600483-C-T, CADD 15.10
- D23E (p.Asp23Glu), gnomAD 17-60600483-C-A, REVEL 0.23, MetaLR 0.22
- V24I (p.Val24Ile), TOPMed rs1477178316, gnomAD rs1477178316, REVEL 0.09, CADD 26.50
- V24F (p.Val24Phe), gnomAD 17-60600484-G-T, REVEL 0.14, MetaLR 0.06
- V24A (p.Val24Ala), gnomAD 17-60600485-T-C, REVEL 0.12, MetaLR 0.05
- V24V (p.Val24Val), gnomAD 17-60600486-T-C, CADD 15.20
- T25L (p.Thr25Leu), gnomAD 17-60600486-TA-T, CADD 28.60
- T25A (p.Thr25Ala), gnomAD 17-60600487-A-G, REVEL 0.07, MetaLR 0.04
- T25P (p.Thr25Pro), gnomAD 17-60600487-A-C, REVEL 0.10, MetaLR 0.06
- T25S (p.Thr25Ser), gnomAD 17-60600487-A-T, REVEL 0.07, MetaLR 0.06
- T25N (p.Thr25Asn), gnomAD 17-60600488-C-A, REVEL 0.12, MetaLR 0.07
- T25T (p.Thr25Thr), gnomAD 17-60600489-T-G, CADD 14.30
- Q26H (p.Gln26His), rs2143606748, ClinGen CA400452329, ClinVar RCV002594005, Uncertain significance, not provided
- Q26* (p.Gln26Ter), gnomAD 17-60600490-C-T, CADD 37.00
- Q26K (p.Gln26Lys), gnomAD 17-60600490-C-A, REVEL 0.08, MetaLR 0.03
- Q26R (p.Gln26Arg), gnomAD 17-60600491-A-G, REVEL 0.10, MetaLR 0.04
- I27F (p.Ile27Phe), ExAC rs753233133, gnomAD rs753233133
- I27M (p.Ile27Met), rs974206177, ClinGen CA292225221, ClinVar RCV003544672, TOPMed rs974206177, REVEL 0.11, CADD 23.60, Conflicting interpretations, Inborn genetic diseases; not provided
- I27S (p.Ile27Ser), gnomAD 17-60600490-CA-C, CADD 29.40
- I27V (p.Ile27Val), gnomAD 17-60600493-A-G, REVEL 0.09, MetaLR 0.02
- I27I (p.Ile27Ile), rs974206177, gnomAD 17-60600495-C-A, CADD 14.00
- V28A (p.Val28Ala), rs2544420665, ClinGen CA400452394, ClinVar RCV002291424, REVEL 0.06, CADD 23.10, Uncertain significance, not provided
- V28I (p.Val28Ile), ExAC rs756726983, gnomAD rs756726983, REVEL 0.07, CADD 20.70
- V28F (p.Val28Phe), gnomAD 17-60600496-G-T, REVEL 0.08, MetaLR 0.04
- V28V (p.Val28Val), gnomAD 17-60600498-T-C, CADD 13.30
- V29A (p.Val29Ala), TOPMed rs1219384750, gnomAD rs1219384750, REVEL 0.07, CADD 27.00
- V29L (p.Val29Leu), gnomAD 17-60600499-G-T, REVEL 0.07, MetaLR 0.03
- V29M (p.Val29Met), gnomAD 17-60600499-G-A, REVEL 0.10, MetaLR 0.07
- V29E (p.Val29Glu), gnomAD 17-60600500-T-A, REVEL 0.12, MetaLR 0.05
- V29V (p.Val29Val), gnomAD 17-60600501-G-T, AlphaMissense 0.08, MetaLR 0.41
- E30D (p.Glu30Asp), 1000Genomes rs16944543, ESP rs16944543, ExAC rs16944543, TOPMed rs16944543, REVEL 0.24, CADD 22.90, Benign
- E30* (p.Glu30Ter), gnomAD 17-60600502-G-T, CADD 38.00
- E30K (p.Glu30Lys), gnomAD 17-60600502-G-A, REVEL 0.22, MetaLR 0.34
- E30V (p.Glu30Val), gnomAD 17-60600503-A-T, REVEL 0.47, AlphaMissense 0.07
- E30G (p.Glu30Gly), gnomAD 17-60600503-A-G, REVEL 0.33, AlphaMissense 0.07
- E30E (p.Glu30Glu), rs16944543, gnomAD 17-60600504-G-A, CADD 11.90
- P31H (p.Pro31His), Ensembl rs1455517774, REVEL 0.12, AlphaMissense 0.06
- P31S (p.Pro31Ser), ExAC rs757366012, TOPMed rs757366012, gnomAD rs757366012, REVEL 0.10, CADD 23.00
- P31T (p.Pro31Thr), gnomAD 17-60600505-C-A, REVEL 0.11, MetaLR 0.20
- P31R (p.Pro31Arg), gnomAD 17-60600506-C-G, REVEL 0.15, AlphaMissense 0.05
- P31L (p.Pro31Leu), gnomAD 17-60600506-C-T, REVEL 0.14, AlphaMissense 0.06
- P31P (p.Pro31Pro), rs779202711, gnomAD 17-60600507-C-A, AlphaMissense 0.18, MetaLR 0.35
- E32K (p.Glu32Lys), gnomAD 17-60600508-G-A, REVEL 0.24, MetaLR 0.24
- E32* (p.Glu32Ter), gnomAD 17-60600508-G-T, CADD 37.00
- E32Q (p.Glu32Gln), gnomAD 17-60600508-G-C, REVEL 0.16, MetaLR 0.28
- E32G (p.Glu32Gly), gnomAD 17-60600509-A-G, REVEL 0.29, AlphaMissense 0.49
- E32E (p.Glu32Glu), rs1222135379, gnomAD 17-60600510-A-G, CADD 12.20
- P33L (p.Pro33Leu), gnomAD rs866963714, REVEL 0.04, CADD 8.29
- P33Q (p.Pro33Gln), gnomAD rs866963714, REVEL 0.11, CADD 17.40
- P33T (p.Pro33Thr), gnomAD 17-60600511-C-A, REVEL 0.07, MetaLR 0.13
- P33P (p.Pro33Pro), rs1312084710, gnomAD 17-60600513-G-A, AlphaMissense 0.91, MetaLR 0.83
- T34M (p.Thr34Met), rs1217818543, ClinGen CA400452576, ClinVar RCV003887536, gnomAD rs1217818543, REVEL 0.07, AlphaMissense 0.09, Uncertain significance, not provided
- T34P (p.Thr34Pro), gnomAD 17-60600514-A-C, REVEL 0.03, MetaLR 0.05
- T34K (p.Thr34Lys), gnomAD 17-60600515-C-A, REVEL 0.03, AlphaMissense 0.11
- T34T (p.Thr34Thr), gnomAD 17-60600516-G-T, CADD 2.60
- A35P (p.Ala35Pro), gnomAD 17-60600517-G-C, REVEL 0.05, MetaLR 0.08
- A35S (p.Ala35Ser), gnomAD 17-60600517-G-T, REVEL 0.03, MetaLR 0.07
- A35T (p.Ala35Thr), gnomAD 17-60600517-G-A, REVEL 0.02, MetaLR 0.06
- A35V (p.Ala35Val), gnomAD 17-60600518-C-T, REVEL 0.04, MetaLR 0.05
- A35D (p.Ala35Asp), gnomAD 17-60600518-C-A, REVEL 0.03, MetaLR 0.06
- A35A (p.Ala35Ala), rs2030180875, gnomAD 17-60600519-T-G, CADD 5.21
- E36G (p.Glu36Gly), gnomAD rs2030180948, REVEL 0.05, AlphaMissense 0.65
- E36* (p.Glu36Ter), gnomAD 17-60600520-G-T, CADD 37.00
- E36K (p.Glu36Lys), gnomAD 17-60600520-G-A, REVEL 0.11, MetaLR 0.09
- E36E (p.Glu36Glu), gnomAD 17-60600522-A-G, CADD 10.20
- E37K (p.Glu37Lys), gnomAD 17-60600523-G-A, REVEL 0.03, MetaLR 0.10
- E37* (p.Glu37Ter), gnomAD 17-60600523-G-T, CADD 37.00
- E37E (p.Glu37Glu), rs746143023, gnomAD 17-60600525-A-G, CADD 11.90
- K38E (p.Lys38Glu), rs1487466505, ClinGen CA400452641, ClinVar RCV003712883, ClinVar RCV005264491, AlphaMissense 0.09, MetaLR 0.05, Conflicting interpretations, Inborn genetic diseases; not provided
- K38Q (p.Lys38Gln), rs1487466505, ClinGen CA400452640, ClinVar RCV003823576, ClinVar RCV004953562, REVEL 0.02, AlphaMissense 0.09, Conflicting interpretations, not provided; Inborn genetic diseases
- K38S (p.Lys38Ser), gnomAD 17-60600523-GA-G, CADD 25.50
- K38R (p.Lys38Arg), gnomAD 17-60600527-A-G, REVEL 0.02, MetaLR 0.06
- K38M (p.Lys38Met), gnomAD 17-60600527-A-T, REVEL 0.02, MetaLR 0.08
- K38N (p.Lys38Asn), gnomAD 17-60600528-G-T, REVEL 0.01, MetaLR 0.06
- P39A (p.Pro39Ala), gnomAD 17-60600529-C-G, REVEL 0.03, MetaLR 0.08
- P39T (p.Pro39Thr), gnomAD 17-60600529-C-A, REVEL 0.02, MetaLR 0.08
- P39L (p.Pro39Leu), gnomAD 17-60600530-C-T, REVEL 0.10, MetaLR 0.06
- P39H (p.Pro39His), gnomAD 17-60600530-C-A, REVEL 0.04, MetaLR 0.06
- P39P (p.Pro39Pro), rs2030181192, gnomAD 17-60600531-C-T, CADD 7.86
- S40L (p.Ser40Leu), NCI-TCGA TCGA novel, REVEL 0.04, CADD 9.92, Variant assessed as somatic; moderate impact.
- S40* (p.Ser40Ter), gnomAD 17-60600533-C-A, CADD 32.00
- S40W (p.Ser40Trp), gnomAD 17-60600533-C-G, REVEL 0.06, MetaLR 0.07
- S40S (p.Ser40Ser), gnomAD 17-60600534-G-T, CADD 9.09
- P41L (p.Pro41Leu), 1000Genomes rs552338842, ExAC rs552338842, gnomAD rs552338842, REVEL 0.04, CADD 18.00
- P41T (p.Pro41Thr), gnomAD 17-60600535-C-A, REVEL 0.01, MetaLR 0.07
- P41S (p.Pro41Ser), gnomAD 17-60600535-C-T, REVEL 0.03, MetaLR 0.06
- P41Q (p.Pro41Gln), gnomAD 17-60600536-C-A, REVEL 0.02, MetaLR 0.08
- P41P (p.Pro41Pro), gnomAD 17-60600537-G-A, CADD 12.40
- R42W (p.Arg42Trp), Ensembl rs1347585114
Public PPM1D analysis runs
- PPM1D analysis run — PPM1D (1,302 variants) — completed 2026-08-19