MDM4 (Protein Mdm4) variants and mutations
MDM4 (also known as Protein Mdm4) is a human protein-coding gene encoding a protein. It suppresses p53 transcriptional and apoptotic activity, cooperating with MDM2 to limit stress responses. Amplification or overexpression can provide an alternative route to p53 inactivation in tumors that retain wild-type TP53. This analysis covers 1,013 MDM4 variants and mutations. Of these, 48% have computational variant effect predictions. Disease context includes bone marrow failure syndrome 6, prostate carcinoma, and neurodegenerative disease. Example MDM4 variants include T2A, T2R, and T2S.
Variant analysis overview
- Gene: MDM4
- Protein: Protein Mdm4
- UniProt accession: O15151
- Organism: Homo sapiens
- Variants analyzed: 1013
- Variant scope: all variants
- Completed: 2026-08-22
Variant and mutation evidence
- Variant composition: 906 unspecified-consequence records; 55 synonymous variants; 41 missense variants; 5 frameshift variants; 5 splice-region variants; 2 stop-gained variants
- Prediction scores: 482 variants have prediction scores (48% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: bone marrow failure syndrome 6, prostate carcinoma, neurodegenerative disease, breast carcinoma, triple-negative breast carcinoma, prostate cancer, actinic keratosis, skin basal cell carcinoma, Transitional Meningioma, superficial spreading melanoma, hemangioblastoma, gastric carcinoma.
Protein structure and variant hotspots
- Protein features: 1 domains; 2 post-translational modification sites.
- Structural context: 215 variants have structural context.
- PTM context: 9 variants overlap post-translational modification sites.
- Experimental data: 31 protein positions have experimental scores. Source: MDM4 Zinc finger, RanBP2-type domain domainome 1.0.
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, MaveDB, LitVar.
Notable MDM4 variants
Examples include T2A, T2R, T2S, T2T, S3*, S3L, S3P, S3T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- T2A (p.Thr2Ala), TOPMed rs1382884218, gnomAD rs1382884218, REVEL 0.05, CADD 19.40
- T2R (p.Thr2Arg), Ensembl rs2102313560
- T2S (p.Thr2Ser), rs1382884218, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65798, TOPMed rs1382884218, REVEL 0.05, CADD 18.50, Variant assessed as somatic; moderate impact.
- T2T (p.Thr2Thr), rs758733517, gnomAD 1-204525524-A-G, CADD 8.12
- S3* (p.Ser3Ter), Ensembl rs2102313603
- S3L (p.Ser3Leu), Ensembl rs2102313603
- S3P (p.Ser3Pro), Ensembl rs2102313592
- S3T (p.Ser3Thr), gnomAD 1-204525525-T-A, REVEL 0.04, CADD 18.80
- S3S (p.Ser3Ser), rs764353353, gnomAD 1-204525527-A-G, CADD 8.90
- F4I (p.Phe4Ile), Ensembl rs2102313631
- S5C (p.Ser5Cys), Ensembl rs2102313657
- S5F (p.Ser5Phe), cosmic curated COSV65798, Ensembl rs2102313657, REVEL 0.13, CADD 25.80
- S5P (p.Ser5Pro), gnomAD 1-204525527-AT-A, CADD 18.90
- T6A (p.Thr6Ala), TOPMed rs558828094, gnomAD rs558828094, REVEL 0.09, CADD 16.00
- T6S (p.Thr6Ser), Ensembl rs2102313713, REVEL 0.04, CADD 15.80
- T6P (p.Thr6Pro), gnomAD 1-204525534-A-C, REVEL 0.13, CADD 23.10
- T6T (p.Thr6Thr), rs752177145, gnomAD 1-204525536-C-G, CADD 5.95
- S7F (p.Ser7Phe), NCI-TCGA TCGA novel, Ensembl rs2102313762, Variant assessed as somatic; moderate impact.
- S7S (p.Ser7Ser), gnomAD 1-204525539-T-C, CADD 12.10
- A8D (p.Ala8Asp), TOPMed rs1660043113, gnomAD rs1660043113
- A8G (p.Ala8Gly), TOPMed rs1660043113, gnomAD rs1660043113, REVEL 0.09, CADD 22.90
- A8P (p.Ala8Pro), 1000Genomes rs115828402, ESP rs115828402, ExAC rs115828402, TOPMed rs115828402, REVEL 0.10, CADD 25.40, Benign
- A8T (p.Ala8Thr), rs115828402, ClinGen CA1348462, ClinVar RCV000881022, 1000Genomes rs115828402, REVEL 0.12, CADD 20.70, Benign, not provided
- A8A (p.Ala8Ala), rs2102313810, gnomAD 1-204525542-T-C, CADD 12.50
- Q9* (p.Gln9Ter), gnomAD rs1202317431
- Q9E (p.Gln9Glu), gnomAD rs1202317431, REVEL 0.03, CADD 22.60
- Q9H (p.Gln9His), Ensembl rs1660043582, cosmic curated COSV65797
- Q9K (p.Gln9Lys), gnomAD rs1202317431, REVEL 0.01, CADD 21.40
- Q9L (p.Gln9Leu), Ensembl rs2102313862
- C10S (p.Cys10Ser), Ensembl rs2102313904
- C10Y (p.Cys10Tyr), Ensembl rs2102313904
- S11A (p.Ser11Ala), Ensembl rs2102313919
- S11L (p.Ser11Leu), Ensembl rs2102313935
- S11P (p.Ser11Pro), Ensembl rs2102313919
- S11S (p.Ser11Ser), gnomAD 1-204525551-A-G, CADD 10.90
- T12A (p.Thr12Ala), TOPMed rs905303517, gnomAD rs905303517, REVEL 0.07, CADD 10.70
- T12I (p.Thr12Ile), Ensembl rs2102313975, CADD 6.48
- T12K (p.Thr12Lys), Ensembl rs2102313975, CADD 3.88
- T12P (p.Thr12Pro), TOPMed rs905303517, gnomAD rs905303517, REVEL 0.05, CADD 16.50
- T12S (p.Thr12Ser), cosmic curated COSV65798, TOPMed rs905303517, gnomAD rs905303517, CADD 10.50
- T12T (p.Thr12Thr), gnomAD 1-204525554-A-G, CADD 7.82
- S13F (p.Ser13Phe), Ensembl rs2102314012
- S13Y (p.Ser13Tyr), Ensembl rs2102314012
- S13S (p.Ser13Ser), gnomAD 1-204525557-T-C, CADD 12.60
- D14E (p.Asp14Glu), Ensembl rs2102314068
- D14G (p.Asp14Gly), Ensembl rs1660044128, REVEL 0.02, CADD 20.30
- D14H (p.Asp14His), cosmic curated COSV65798, Ensembl rs2102314034
- D14N (p.Asp14Asn), Ensembl rs2102314034
- D14V (p.Asp14Val), Ensembl rs1660044128
- S15N (p.Ser15Asn), Ensembl rs2102314085
- S15R (p.Ser15Arg), TOPMed rs1436586294, gnomAD rs1436586294
- S15T (p.Ser15Thr), Ensembl rs2102314085, REVEL 0.05, CADD 16.90
- S15G (p.Ser15Gly), gnomAD 1-204525561-A-G, REVEL 0.04, CADD 19.50
- S15S (p.Ser15Ser), rs1436586294, gnomAD 1-204525563-T-C, CADD 12.20
- A16D (p.Ala16Asp), Ensembl rs2102314152, REVEL 0.07, CADD 25.40
- A16G (p.Ala16Gly), Ensembl rs2102314152
- A16P (p.Ala16Pro), ExAC rs780902661, REVEL 0.14, CADD 24.70
- A16S (p.Ala16Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A16T (p.Ala16Thr), ExAC rs780902661
- A16V (p.Ala16Val), Ensembl rs2102314152
- A16A (p.Ala16Ala), gnomAD 1-204525566-T-C, CADD 12.80
- C17F (p.Cys17Phe), Ensembl rs2102314214
- C17R (p.Cys17Arg), TOPMed rs1249145025, REVEL 0.03, CADD 22.80
- C17S (p.Cys17Ser), Ensembl rs2102314214
- C17W (p.Cys17Trp), ExAC rs745325502, TOPMed rs745325502, gnomAD rs745325502
- C17Y (p.Cys17Tyr), Ensembl rs2102314214, REVEL 0.10, CADD 24.80
- C17C (p.Cys17Cys), rs745325502, gnomAD 1-204525569-C-T, CADD 9.51
- R18G (p.Arg18Gly), Ensembl rs754269993, REVEL 0.06, CADD 22.00
- R18S (p.Arg18Ser), Ensembl rs2102314293, NCI-TCGA TCGA novel, REVEL 0.02, CADD 22.80, Variant assessed as somatic; moderate impact.
- R18T (p.Arg18Thr), Ensembl rs2102314276
- R18W (p.Arg18Trp), Ensembl rs754269993
- R18M (p.Arg18Met), gnomAD 1-204525571-G-T, REVEL 0.10, CADD 27.10
- R18K (p.Arg18Lys), gnomAD 1-204525571-G-A, REVEL 0.04, CADD 22.70
- R18R (p.Arg18Arg), rs2102314293, gnomAD 1-204525572-G-A, CADD 10.30
- I19F (p.Ile19Phe), Ensembl rs2102314312
- I19L (p.Ile19Leu), Ensembl rs2102314312
- I19M (p.Ile19Met), cosmic curated COSV10091, 1000Genomes rs148900701, ESP rs148900701, ExAC rs148900701, REVEL 0.03, CADD 21.00
- I19N (p.Ile19Asn), TOPMed rs1185480236, gnomAD rs1185480236
- I19S (p.Ile19Ser), TOPMed rs1185480236, gnomAD rs1185480236, REVEL 0.07, CADD 22.00
- S20F (p.Ser20Phe), cosmic curated COSV65797, ExAC rs779696576, REVEL 0.04, CADD 23.60
- S20S (p.Ser20Ser), gnomAD 1-204525578-T-C, CADD 9.36
- P21A (p.Pro21Ala), TOPMed rs1481232207, gnomAD rs1481232207, REVEL 0.02, CADD 0.15
- P21H (p.Pro21His), Ensembl rs2102314425, REVEL 0.05, CADD 22.60, Uncertain significance
- P21L (p.Pro21Leu), Ensembl rs2102314425, Uncertain significance
- P21R (p.Pro21Arg), rs2102314425, ClinGen CA344360310, ClinVar RCV004421476, Ensembl rs2102314425, REVEL 0.05, CADD 22.30, Uncertain significance, not specified
- P21S (p.Pro21Ser), cosmic curated COSV10442, TOPMed rs1481232207, gnomAD rs1481232207, REVEL 0.03, CADD 0.07
- P21T (p.Pro21Thr), cosmic curated COSV10592, TOPMed rs1481232207, gnomAD rs1481232207, REVEL 0.04, CADD 0.07
- P21P (p.Pro21Pro), gnomAD 1-204525581-T-C, CADD 9.13
- G22* (p.Gly22Ter), ExAC rs748876366, gnomAD rs748876366
- G22A (p.Gly22Ala), TOPMed rs1660048593
- G22E (p.Gly22Glu), TOPMed rs1660048593
- G22R (p.Gly22Arg), ExAC rs748876366, gnomAD rs748876366, REVEL 0.10, CADD 23.10
- G22V (p.Gly22Val), TOPMed rs1660048593, CADD 4.19
- G22T (p.Gly22Thr), gnomAD 1-204525581-TGG-T, CADD 32.00
- Q23E (p.Gln23Glu), gnomAD rs1428358052
- Q23H (p.Gln23His), ExAC rs773983041, gnomAD rs773983041, REVEL 0.05, CADD 17.90
- Q23K (p.Gln23Lys), gnomAD rs1428358052, REVEL 0.03, CADD 21.50
- Q23L (p.Gln23Leu), ESP rs369657471, ExAC rs369657471, TOPMed rs369657471, gnomAD rs369657471, REVEL 0.07, CADD 23.20, Uncertain significance, not specified
- Q23P (p.Gln23Pro), ESP rs369657471, ExAC rs369657471, TOPMed rs369657471, gnomAD rs369657471, REVEL 0.07, CADD 20.70
- Q23Q (p.Gln23Gln), gnomAD 1-204525587-A-G, CADD 6.29
- I24F (p.Ile24Phe), gnomAD rs1345762411
- I24M (p.Ile24Met), cosmic curated COSV65798, Ensembl rs2102314635
- I24N (p.Ile24Asn), Ensembl rs2102314618
- I24V (p.Ile24Val), gnomAD rs1345762411, REVEL 0.06, CADD 13.50
- I24T (p.Ile24Thr), gnomAD 1-204525589-T-C, REVEL 0.02, CADD 12.30
- I24I (p.Ile24Ile), rs2102314635, gnomAD 1-204525590-C-A, CADD 8.56
- N25I (p.Asn25Ile), gnomAD rs1011975434, REVEL 0.03, CADD 17.50
- N25K (p.Asn25Lys), TOPMed rs1056671167, gnomAD rs1056671167
- N25Y (p.Asn25Tyr), Ensembl rs2102314659
- N25S (p.Asn25Ser), gnomAD 1-204525592-A-G, REVEL 0.03, CADD 9.15
- N25N (p.Asn25Asn), rs1056671167, gnomAD 1-204525593-T-C, CADD 7.02
- Q26* (p.Gln26Ter), Ensembl rs2102314706
- Q26E (p.Gln26Glu), cosmic curated COSV10091, Ensembl rs2102314706
- Q26H (p.Gln26His), Ensembl rs2102314742, REVEL 0.23, CADD 35.00
- Q26K (p.Gln26Lys), Ensembl rs2102314706, REVEL 0.06, CADD 10.80
- Q26L (p.Gln26Leu), Ensembl rs2102314728
- Q26R (p.Gln26Arg), Ensembl rs2102314728, REVEL 0.18, CADD 26.60
- Q26Q (p.Gln26Gln), rs2102314742, gnomAD 1-204525596-G-A, CADD 24.30
- V27E (p.Val27Glu), Ensembl rs2102321141
- V27I (p.Val27Ile), Ensembl rs2102321116, REVEL 0.12, CADD 27.60
- V27L (p.Val27Leu), Ensembl rs2102321116, REVEL 0.31, CADD 33.00
- V27V (p.Val27Val), rs776948959, gnomAD 1-204526362-A-G, CADD 15.80
- R28* (p.Arg28Ter), cosmic curated COSV65798, Ensembl rs2102321169
- R28G (p.Arg28Gly), Ensembl rs2102321169
- R28L (p.Arg28Leu), cosmic curated COSV65797, TOPMed rs771203637, REVEL 0.20, CADD 26.90
- R28P (p.Arg28Pro), TOPMed rs771203637
- R28Q (p.Arg28Gln), cosmic curated COSV65797, TOPMed rs771203637
- K30* (p.Lys30Ter), Ensembl rs2102321264
- K30I (p.Lys30Ile), Ensembl rs2102321284
- K30N (p.Lys30Asn), Ensembl rs1572460727
- L31P (p.Leu31Pro), Ensembl rs2102321344
- L31V (p.Leu31Val), Ensembl rs2102321313
- P32A (p.Pro32Ala), Ensembl rs2102321387
- P32L (p.Pro32Leu), rs181171068, ClinGen CA1348493, ClinVar RCV003414703, 1000Genomes rs181171068, REVEL 0.13, CADD 22.40, Likely benign, not provided
- P32R (p.Pro32Arg), 1000Genomes rs181171068, ExAC rs181171068, TOPMed rs181171068, gnomAD rs181171068, REVEL 0.14, CADD 24.90, Likely benign
- P32S (p.Pro32Ser), Ensembl rs2102321387
- P32P (p.Pro32Pro), rs778790692, gnomAD 1-204526377-G-A, CADD 8.08
- L33H (p.Leu33His), Ensembl rs2102321479
- L33P (p.Leu33Pro), Ensembl rs2102321479
- L33V (p.Leu33Val), Ensembl rs2102321465
- L33L (p.Leu33Leu), rs2102321500, gnomAD 1-204526380-T-A, CADD 11.50
- L34* (p.Leu34Ter), Ensembl rs2102321547
- L34F (p.Leu34Phe), cosmic curated COSV65797, Ensembl rs2102321571
- L34S (p.Leu34Ser), Ensembl rs2102321547
- L34L (p.Leu34Leu), rs747896110, gnomAD 1-204526381-T-C, CADD 8.99
- K35* (p.Lys35Ter), Ensembl rs2102321607
- K35M (p.Lys35Met), Ensembl rs2102321616
- K35N (p.Lys35Asn), Ensembl rs2102321639
- K35R (p.Lys35Arg), Ensembl rs2102321616
- I36V (p.Ile36Val), TOPMed rs983496580, REVEL 0.19, CADD 22.60
- L37* (p.Leu37Ter), Ensembl rs2102321682
- L37F (p.Leu37Phe), gnomAD rs1387053905
- L37V (p.Leu37Val), Ensembl rs2102321671
- L37L (p.Leu37Leu), rs1387053905, gnomAD 1-204526392-G-A, CADD 10.80
- H38L (p.His38Leu), Ensembl rs2102321724
- H38R (p.His38Arg), NCI-TCGA TCGA novel, Ensembl rs2102321724, Variant assessed as somatic; moderate impact.
- H38H (p.His38His), rs2102321748, gnomAD 1-204526395-T-C, CADD 8.02
- A39G (p.Ala39Gly), 1000Genomes rs1660150338, REVEL 0.03, CADD 22.90
- A39P (p.Ala39Pro), Ensembl rs2102321768
- A39T (p.Ala39Thr), Ensembl rs2102321768
- A39V (p.Ala39Val), 1000Genomes rs1660150338, REVEL 0.02, CADD 22.20
- A39A (p.Ala39Ala), rs2102321810, gnomAD 1-204526398-A-T, CADD 13.00
- A40E (p.Ala40Glu), Ensembl rs2102321850
- A40G (p.Ala40Gly), Ensembl rs2102321850
- A40P (p.Ala40Pro), Ensembl rs2102321831
- A40T (p.Ala40Thr), Ensembl rs2102321831
- A40V (p.Ala40Val), Ensembl rs2102321850, REVEL 0.21, CADD 27.70
- A40A (p.Ala40Ala), rs145504896, gnomAD 1-204526401-A-C, CADD 11.10
- G41A (p.Gly41Ala), Ensembl rs2102321929
- G41C (p.Gly41Cys), cosmic curated COSV10091, Ensembl rs2102321892
- G41D (p.Gly41Asp), Ensembl rs2102321929
- G41R (p.Gly41Arg), Ensembl rs2102321892
- G41S (p.Gly41Ser), Ensembl rs2102321892
- G41G (p.Gly41Gly), rs2102321943, gnomAD 1-204526404-T-G, CADD 13.70
- A42E (p.Ala42Glu), Ensembl rs2102321973
- A42G (p.Ala42Gly), Ensembl rs2102321973
- A42T (p.Ala42Thr), Ensembl rs2102321958
- A42V (p.Ala42Val), Ensembl rs2102321973
- A42A (p.Ala42Ala), rs777631589, gnomAD 1-204526407-G-T, CADD 4.47
- Q43L (p.Gln43Leu), Ensembl rs2102322030
Public MDM4 analysis runs
- MDM4 analysis run — MDM4 (1,013 variants) — completed 2026-08-22