MDM2 (E3 ubiquitin-protein ligase Mdm2) variants and mutations
MDM2 (also known as E3 ubiquitin-protein ligase Mdm2) is a human protein-coding gene encoding an e3 ubiquitin-protein ligase protein. It restrains the p53 pathway by binding p53 and promoting its ubiquitination and degradation. Amplification or overexpression can disable p53-mediated tumor suppression without TP53 mutation and is therefore a major therapeutic target in cancer. This analysis covers 382 MDM2 variants and mutations. Of these, 45% have computational variant effect predictions. Disease context includes Lessel-Kubisch syndrome, cancer, and prostate carcinoma. Example MDM2 variants include C2R, C2F, and N3S.
Variant analysis overview
- Gene: MDM2
- Protein: E3 ubiquitin-protein ligase Mdm2
- UniProt accession: Q00987
- Organism: Homo sapiens
- Variants analyzed: 382
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 240 unspecified-consequence records; 95 missense variants; 33 synonymous variants; 3 splice-region variants; 5 frameshift variants; 1 in-frame deletions; 1 stop-gained variants; 4 substitution
- Prediction scores: 172 variants have prediction scores (45% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Lessel-Kubisch syndrome, cancer, prostate carcinoma, Li-Fraumeni syndrome, skin basal cell carcinoma, lymphoid neoplasm, breast ductal adenocarcinoma, hemangioblastoma, skin squamous cell carcinoma, nodular malignant melanoma, hepatobiliary neoplasm, carcinoma of liver and intrahepatic biliary tract.
Protein structure and variant hotspots
- Protein features: 1 domains; 4 binding sites; 13 post-translational modification sites.
- Structural context: 136 variants have structural context.
- PTM context: 9 variants overlap post-translational modification sites.
- Experimental data: 29 protein positions have experimental scores. Source: MDM2 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 MDM2 variants
Examples include C2R, C2F, N3S, T4I, N5K, N5H, N5S, N5T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- C2R (p.Cys2Arg), NCI-TCGA Cosmic COSV5069, cosmic curated COSV50699, Variant assessed as somatic; moderate impact.
- C2F (p.Cys2Phe), gnomAD 12-68809216-G-T, REVEL 0.27, CADD 27.20
- N3S (p.Asn3Ser), cosmic curated COSV50698
- T4I (p.Thr4Ile), cosmic curated COSV10804, gnomAD rs1347430167
- N5K (p.Asn5Lys), gnomAD 12-68809217-C-CA, CADD 32.00
- N5H (p.Asn5His), gnomAD 12-68809218-A-C, REVEL 0.12, CADD 28.50
- N5S (p.Asn5Ser), gnomAD 12-68809219-A-G, REVEL 0.08, CADD 22.70
- N5T (p.Asn5Thr), gnomAD 12-68809225-A-C, REVEL 0.03, CADD 19.80
- M6I (p.Met6Ile), cosmic curated COSV50700
- S7C (p.Ser7Cys), cosmic curated COSV50697
- S7T (p.Ser7Thr), rs1411053475, gnomAD 12-68808488-G-C, CADD 9.83, PolyPhen-2 0.03
- S7N (p.Ser7Asn), rs1411053475, gnomAD 12-68808488-G-A, CADD 13.10, PolyPhen-2 0.05
- S7S (p.Ser7Ser), rs868314073, gnomAD 12-68808489-C-T, CADD 23.10
- V8L (p.Val8Leu), rs1390633476, gnomAD 12-68808481-G-T, CADD 15.10, PolyPhen-2 0.18
- T10A (p.Thr10Ala), rs1450828029, ClinGen CA385702907, NCI-TCGA Cosmic COSV9925, cosmic curated COSV99254, REVEL 0.11, CADD 24.70, Uncertain significance, Accelerated tumor formation, susceptibility to
- T10I (p.Thr10Ile), cosmic curated COSV50699, TOPMed rs1880642775, REVEL 0.12, CADD 22.90
- T10S (p.Thr10Ser), cosmic curated COSV10585, NCI-TCGA Cosmic COSV9925, REVEL 0.08, CADD 24.40, Variant assessed as somatic; moderate impact.
- T10N (p.Thr10Asn), gnomAD 12-68809222-C-A, REVEL 0.10, CADD 25.50
- T10T (p.Thr10Thr), gnomAD 12-68809223-C-T, CADD 16.20
- D11N (p.Asp11Asn), cosmic curated COSV50706
- D11G (p.Asp11Gly), rs746284240, gnomAD 12-68809243-A-G, REVEL 0.10, CADD 25.30
- D11D (p.Asp11Asp), rs199663735, gnomAD 12-68809244-T-C, CADD 10.70
- G12R (p.Gly12Arg), cosmic curated COSV99254
- V14I (p.Val14Ile), rs2136105539, gnomAD 12-68809233-G-A, REVEL 0.11, CADD 22.70
- V20del (p.Val20del), rs1367482093, gnomAD 12-68809249-CTGT-, CADD 18.90
- V14V (p.Val14Val), rs1880645795, gnomAD 12-68809253-A-T, CADD 13.80
- T16A (p.Thr16Ala), rs1450828029, gnomAD 12-68809239-A-G, REVEL 0.11, CADD 23.30
- T16I (p.Thr16Ile), rs1880642775, gnomAD 12-68809240-C-T, REVEL 0.23, CADD 27.20
- T16S (p.Thr16Ser), rs1880642775, gnomAD 12-68809240-C-G, REVEL 0.16, CADD 26.20
- S17L (p.Ser17Leu), cosmic curated COSV10509
- S17F (p.Ser17Phe), rs781195441, gnomAD 12-68809231-C-T, REVEL 0.15, CADD 28.70
- S17S (p.Ser17Ser), rs1457088132, gnomAD 12-68809232-T-C, CADD 16.30
- I19T (p.Ile19Thr), rs771046322, gnomAD 12-68809267-T-C, REVEL 0.19, CADD 25.00
- P20S (p.Pro20Ser), rs577736495, gnomAD 12-68809236-C-T, REVEL 0.03, CADD 13.80
- P20L (p.Pro20Leu), rs201821879, gnomAD 12-68809237-C-T, REVEL 0.06, CADD 22.80
- P20P (p.Pro20Pro), rs1880641896, gnomAD 12-68809238-T-C, CADD 14.20
- A21T (p.Ala21Thr), cosmic curated COSV10585
- A21V (p.Ala21Val), rs991848363, gnomAD 12-68809249-C-T, REVEL 0.11, CADD 23.40
- S22S (p.Ser22Ser), gnomAD 12-68809262-A-T, CADD 14.60
- E23K (p.Glu23Lys), rs1361311287, ClinGen CA385702983, cosmic curated COSV50699, ClinVar RCV001894478, AlphaMissense 0.20, MetaLR 0.33, Uncertain significance, Accelerated tumor formation, susceptibility to
- Q24K (p.Gln24Lys), rs2499096284, ClinGen CA385702991, ClinVar RCV003066042, Uncertain significance, Accelerated tumor formation, susceptibility to
- Q24Q (p.Gln24Gln), rs1880647399, gnomAD 12-68809265-G-A, CADD 14.50
- Q24R (p.Gln24Arg), gnomAD 12-68809282-A-G, REVEL 0.18, CADD 29.10
- E25Q (p.Glu25Gln), rs1246173207, ClinGen CA385703000, ClinVar RCV001894316, ClinVar RCV004641713, AlphaMissense 0.28, MetaLR 0.28, Uncertain significance, not specified; Accelerated tumor formation, susceptibility to
- E25K (p.Glu25Lys), rs1361311287, gnomAD 12-68809278-G-A, REVEL 0.11, AlphaMissense 0.20
- E25E (p.Glu25Glu), rs774382161, gnomAD 12-68809280-A-G, CADD 12.70
- E25G (p.Glu25Gly), rs746439458, gnomAD 12-68809285-A-G, REVEL 0.21, CADD 32.00
- T26P (p.Thr26Pro), cosmic curated COSV99254
- T26A (p.Thr26Ala), rs749406013, gnomAD 12-68809257-A-G, REVEL 0.10, CADD 22.50
- T26S (p.Thr26Ser), gnomAD 12-68809257-A-T, REVEL 0.10, CADD 21.00
- T26T (p.Thr26Thr), gnomAD 12-68809259-C-T, CADD 15.40
- T26N (p.Thr26Asn), rs772554005, gnomAD 12-68809288-C-A, REVEL 0.06, CADD 22.50
- T26I (p.Thr26Ile), rs772554005, gnomAD 12-68809288-C-T, REVEL 0.09, CADD 23.80
- V28I (p.Val28Ile), rs1470334779, gnomAD 12-68813554-G-A, REVEL 0.20, CADD 29.90
- R29R (p.Arg29Arg), gnomAD 12-68808486-G-A, CADD 5.50
- R29G (p.Arg29Gly), rs1880557549, gnomAD 12-68808490-A-G, CADD 24.20, PolyPhen-2 0.10
- R29S (p.Arg29Ser), gnomAD 12-68809208-G-T, CADD 25.40, PolyPhen-2 0.10
- R29K (p.Arg29Lys), rs1330733959, gnomAD 12-68813558-G-A, REVEL 0.10, CADD 22.20
- P30S (p.Pro30Ser), gnomAD 12-68809269-C-T, REVEL 0.11, CADD 22.60
- P32S (p.Pro32Ser), cosmic curated COSV50705
- P32T (p.Pro32Thr), gnomAD 12-68813566-C-A, REVEL 0.24, CADD 23.60
- P32P (p.Pro32Pro), gnomAD 12-68813568-A-G, CADD 13.70
- P32A (p.Pro32Ala), gnomAD 12-68815649-C-G, CADD 6.89
- P32L (p.Pro32Leu), gnomAD 12-68815650-C-T, CADD 8.06
- P32H (p.Pro32His), gnomAD 12-68815650-C-A, CADD 7.36
- L33V (p.Leu33Val), rs1295572460, gnomAD 12-68809290-C-G, REVEL 0.14, CADD 29.50
- L33L (p.Leu33Leu), gnomAD 12-68809292-G-A, CADD 25.10
- L35F (p.Leu35Phe), cosmic curated COSV50703
- K36R (p.Lys36Arg), cosmic curated COSV50698
- K36K (p.Lys36Lys), gnomAD 12-68813565-G-A, CADD 10.60
- K36N (p.Lys36Asn), gnomAD 12-68813565-G-T, REVEL 0.31, CADD 23.00
- L38I (p.Leu38Ile), gnomAD 12-68813572-C-A, REVEL 0.22, CADD 24.40
- L38S (p.Leu38Ser), rs1226240451, gnomAD 12-68813576-T-C, REVEL 0.33, CADD 25.20
- L38L (p.Leu38Leu), gnomAD 12-68813577-G-A, CADD 15.20
- S40A (p.Ser40Ala), gnomAD 12-68813590-T-G, REVEL 0.06, CADD 20.00
- S40E (p.Ser40Glu), rs1290275052, gnomAD 12-68815631-T-TG, CADD 5.82
- S40C (p.Ser40Cys), gnomAD 12-68815634-A-T, CADD 5.39
- S40G (p.Ser40Gly), rs945637232, gnomAD 12-68815634-A-G, CADD 8.56
- S40N (p.Ser40Asn), rs763864070, gnomAD 12-68815635-G-A, CADD 5.75
- S40S (p.Ser40Ser), gnomAD 12-68815636-T-C, CADD 5.40
- G42C (p.Gly42Cys), cosmic curated COSV50701
- A43E (p.Ala43Glu), cosmic curated COSV50697
- A43V (p.Ala43Val), rs2136114136, gnomAD 12-68813600-C-T, REVEL 0.38, CADD 27.70
- A43A (p.Ala43Ala), rs376784402, gnomAD 12-68813601-A-G, CADD 11.80
- A43L (p.Ala43Leu), gnomAD 12-68815670-TG-T, CADD 5.63
- A43P (p.Ala43Pro), gnomAD 12-68815673-G-C, CADD 6.78
- A43T (p.Ala43Thr), gnomAD 12-68815673-G-A, CADD 9.77
- A43S (p.Ala43Ser), gnomAD 12-68815673-G-T, CADD 6.66
- A43D (p.Ala43Asp), gnomAD 12-68815674-C-A, CADD 7.82
- Q44K (p.Gln44Lys), cosmic curated COSV50699
- Q44Q (p.Gln44Gln), gnomAD 12-68813604-A-G, CADD 12.20
- D46E (p.Asp46Glu), rs563762756, gnomAD 12-68813610-C-G, REVEL 0.11, CADD 16.40
- D46D (p.Asp46Asp), rs563762756, gnomAD 12-68813610-C-T, CADD 11.80
- T49S (p.Thr49Ser), rs1487823798, gnomAD 12-68813611-A-T, REVEL 0.12, CADD 23.40
- T49T (p.Thr49Thr), rs1234240793, gnomAD 12-68813613-T-C, CADD 11.50
- K51K (p.Lys51Lys), gnomAD 12-68813607-A-G, CADD 10.10
- V53S (p.Val53Ser), gnomAD 12-68815656-TG-T, CADD 4.57
- V53A (p.Val53Ala), gnomAD 12-68815659-T-C, CADD 4.15
- V53G (p.Val53Gly), gnomAD 12-68815659-T-G, CADD 5.24
- V53V (p.Val53Val), gnomAD 12-68815660-C-A, CADD 5.56
- L54V (p.Leu54Val), rs2499133105, ClinGen CA385704028, ClinVar RCV003629790, Uncertain significance, Accelerated tumor formation, susceptibility to
- F55L (p.Phe55Leu), gnomAD 12-68815637-T-C, CADD 5.34
- F55F (p.Phe55Phe), gnomAD 12-68815639-C-T, CADD 7.29
- Y56C (p.Tyr56Cys), cosmic curated COSV10804
- Y56F (p.Tyr56Phe), rs2136121383, ClinGen CA385704045, cosmic curated COSV50700, ClinVar RCV001895953, AlphaMissense 0.13, MetaLR 0.35, Uncertain significance, Accelerated tumor formation, susceptibility to
- Y56Y (p.Tyr56Tyr), rs997464909, gnomAD 12-68813616-T-C, CADD 2.22
- L57L (p.Leu57Leu), rs1158239106, gnomAD 12-68815646-T-C, CADD 9.41
- L57S (p.Leu57Ser), gnomAD 12-68815647-T-C, CADD 9.06
- L57F (p.Leu57Phe), rs1212534918, gnomAD 12-68815648-G-T, CADD 7.20
- G58R (p.Gly58Arg), gnomAD 12-68815679-G-A, CADD 6.02
- G58W (p.Gly58Trp), gnomAD 12-68815679-G-T, CADD 6.14
- G58V (p.Gly58Val), gnomAD 12-68815680-G-T, CADD 6.30
- G58E (p.Gly58Glu), rs115750302, gnomAD 12-68815680-G-A, CADD 7.21
- G58G (p.Gly58Gly), rs1211816988, gnomAD 12-68815681-G-A, CADD 7.16
- M62V (p.Met62Val), rs898137672, gnomAD 12-68815643-A-G, CADD 8.40
- M62L (p.Met62Leu), gnomAD 12-68815643-A-C, CADD 7.87
- M62I (p.Met62Ile), gnomAD 12-68815645-G-T, CADD 7.92
- T63A (p.Thr63Ala), rs1358766276, gnomAD 12-68815640-A-G, CADD 8.10
- T63S (p.Thr63Ser), gnomAD 12-68815640-A-T, CADD 7.37
- T63N (p.Thr63Asn), gnomAD 12-68815641-C-A, CADD 6.01
- T63I (p.Thr63Ile), gnomAD 12-68815641-C-T, CADD 7.36
- T63T (p.Thr63Thr), rs1043962874, gnomAD 12-68815642-T-C, CADD 8.64
- K64N (p.Lys64Asn), cosmic curated COSV10941
- R65Q (p.Arg65Gln), rs1385829631, ClinGen CA385704109, NCI-TCGA Cosmic COSV5069, cosmic curated COSV50697, AlphaMissense 0.94, MetaLR 0.12, Uncertain significance, Accelerated tumor formation, susceptibility to
- R65G (p.Arg65Gly), gnomAD 12-68815628-A-G, CADD 7.00
- R65I (p.Arg65Ile), gnomAD 12-68815629-G-T, CADD 5.14
- R65K (p.Arg65Lys), gnomAD 12-68815629-G-A, CADD 4.55
- R65R (p.Arg65Arg), rs1203441887, gnomAD 12-68815630-A-G, CADD 5.53
- R65S (p.Arg65Ser), gnomAD 12-68815630-A-T, CADD 5.62
- R65M (p.Arg65Met), gnomAD 12-68815653-G-T, CADD 6.25
- R65W (p.Arg65Trp), rs1391933190, gnomAD 12-68815694-C-T, CADD 1.08
- R65L (p.Arg65Leu), rs1447652328, gnomAD 12-68815695-G-T, CADD 1.19
- L66L (p.Leu66Leu), gnomAD 12-68815655-C-T, CADD 7.21
- L66M (p.Leu66Met), gnomAD 12-68815655-C-A, CADD 5.31
- L66P (p.Leu66Pro), gnomAD 12-68815656-T-C, CADD 6.86
- L66S (p.Leu66Ser), gnomAD 12-68815689-T-C, CADD 6.39
- D68N (p.Asp68Asn), cosmic curated COSV50703
- K70Q (p.Lys70Gln), rs774100788, ClinGen CA6678599, cosmic curated COSV50698, ClinVar RCV001947987, AlphaMissense 0.13, MetaLR 0.16, Uncertain significance, Accelerated tumor formation, susceptibility to
- K70R (p.Lys70Arg), cosmic curated COSV10457
- K70E (p.Lys70Glu), rs1330401266, gnomAD 12-68815703-A-G, CADD 5.86
- K70I (p.Lys70Ile), gnomAD 12-68815704-A-T, CADD 5.93
- Q71* (p.Gln71Ter), cosmic curated COSV10509
- Q71K (p.Gln71Lys), rs904057030, gnomAD 12-68815676-C-A, CADD 7.86
- Q71R (p.Gln71Arg), rs1881307285, gnomAD 12-68815677-A-G, CADD 9.35
- Q71Q (p.Gln71Gln), gnomAD 12-68815678-A-G, CADD 8.19
- I74V (p.Ile74Val), gnomAD 12-68815682-A-G, CADD 10.90
- I74T (p.Ile74Thr), gnomAD 12-68815683-T-C, CADD 5.56
- I74I (p.Ile74Ile), gnomAD 12-68815684-C-A, CADD 7.49
- V75C (p.Val75Cys), gnomAD 12-68815702-TA-T, CADD 2.41
- V75M (p.Val75Met), gnomAD 12-68815706-G-A, CADD 5.33
- V75A (p.Val75Ala), gnomAD 12-68815707-T-C, CADD 6.96
- V75V (p.Val75Val), gnomAD 12-68815708-G-A, CADD 3.71
- C77R (p.Cys77Arg), gnomAD 12-68815685-T-C, CADD 5.30
- C77Y (p.Cys77Tyr), gnomAD 12-68815686-G-A, CADD 5.20
- C77F (p.Cys77Phe), gnomAD 12-68815686-G-T, CADD 4.73
- C77C (p.Cys77Cys), gnomAD 12-68815687-C-T, CADD 5.29
- C77* (p.Cys77Ter), gnomAD 12-68815687-C-A, CADD 3.24
- S78P (p.Ser78Pro), gnomAD 12-68815667-T-C, CADD 10.60
- S78T (p.Ser78Thr), gnomAD 12-68815667-T-A, CADD 8.56
- S78F (p.Ser78Phe), rs1881306388, gnomAD 12-68815668-C-T, CADD 7.01
- S78Y (p.Ser78Tyr), gnomAD 12-68815668-C-A, CADD 6.38
- S78S (p.Ser78Ser), gnomAD 12-68815669-C-T, CADD 4.46
- N79D (p.Asn79Asp), NCI-TCGA Cosmic COSV5070, cosmic curated COSV50703, Variant assessed as somatic; moderate impact.
- N79S (p.Asn79Ser), gnomAD 12-68815665-A-G, CADD 7.28
- N79N (p.Asn79Asn), gnomAD 12-68815666-C-T, CADD 2.56
- D80Y (p.Asp80Tyr), NCI-TCGA Cosmic COSV5070, cosmic curated COSV50700, Ensembl rs2136121646, Variant assessed as somatic; moderate impact.
- L81I (p.Leu81Ile), cosmic curated COSV50698, gnomAD rs1229293747
- L81V (p.Leu81Val), cosmic curated COSV10724, gnomAD rs1229293747
- L85F (p.Leu85Phe), cosmic curated COSV50699
- L85V (p.Leu85Val), NCI-TCGA Cosmic COSV5069, cosmic curated COSV50698, Variant assessed as somatic; moderate impact.
- V88M (p.Val88Met), cosmic curated COSV50697, Ensembl rs2136121722
- P89S (p.Pro89Ser), cosmic curated COSV10958
- P89T (p.Pro89Thr), gnomAD 12-68815691-C-A, CADD 4.28
- P89H (p.Pro89His), gnomAD 12-68815692-C-A, CADD 2.82
- P89L (p.Pro89Leu), rs960728953, gnomAD 12-68815692-C-T, CADD 3.24
- P89R (p.Pro89Arg), rs960728953, gnomAD 12-68815692-C-G, CADD 3.45
- P89P (p.Pro89Pro), gnomAD 12-68815693-T-C, CADD 5.88
- F91L (p.Phe91Leu), rs78419579, Uncertain significance
- S92F (p.Ser92Phe), cosmic curated COSV50700
- H96N (p.His96Asn), cosmic curated COSV10509, Ensembl rs2136121815
Public MDM2 analysis runs
- MDM2 analysis run — MDM2 (382 variants) — completed 2026-08-19