TOP2A (DNA topoisomerase 2-alpha) variants and mutations
TOP2A (also known as DNA topoisomerase 2-alpha) is a human protein-coding gene encoding a DNA topoisomerase 2-alpha protein. It resolves DNA tangles and supercoils by passing one double helix through a transient double-strand break in another, a process essential during replication and chromosome segregation. It is the target of widely used anticancer drugs including anthracyclines and etoposide. This analysis covers 1,866 TOP2A variants and mutations. Of these, 59% have computational variant effect predictions. Disease context includes neoplasm, breast cancer, and acute myeloid leukemia. Example TOP2A variants include M1?, E2*, and E2K.
Variant analysis overview
- Gene: TOP2A
- Protein: DNA topoisomerase 2-alpha
- UniProt accession: P11388
- Organism: Homo sapiens
- Variants analyzed: 1866
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 1,655 unspecified-consequence records; 1 stop lost; 112 missense variants; 70 synonymous variants; 3 stop-gained variants; 9 frameshift variants; 5 in-frame deletions; 3 splice-region variants; 2 in-frame insertions; 1 protein altering variant; 5 substitution
- Prediction scores: 1,107 variants have prediction scores (59% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: neoplasm, breast cancer, acute myeloid leukemia, plasma cell myeloma, small cell lung carcinoma, Kaposi's sarcoma, Hodgkins lymphoma, ovarian cancer, ovarian carcinoma, acute myeloid leukemia by FAB classification, urinary bladder carcinoma, prostate cancer.
Protein structure and variant hotspots
- Protein features: 2 domains; 9 binding sites; 35 post-translational modification sites.
- Structural context: 606 variants have structural context.
- PTM context: 78 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, MaveDB, LitVar.
Notable TOP2A variants
Examples include M1?, E2*, E2K, V3L, S4*, S4T, P5L, Q7*. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; high impact.
- E2* (p.Glu2Ter), TOPMed rs2035411699, gnomAD rs2035411699, CADD 45.00
- E2K (p.Glu2Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- V3L (p.Val3Leu), TOPMed rs902922533, gnomAD rs902922533, REVEL 0.04, CADD 18.70
- S4* (p.Ser4Ter), Ensembl rs2143699919
- S4T (p.Ser4Thr), Ensembl rs2143699924
- P5L (p.Pro5Leu), NCI-TCGA Cosmic COSV7073, gnomAD rs2035411566, REVEL 0.14, CADD 26.10, Variant assessed as somatic; moderate impact.
- Q7* (p.Gln7Ter), Ensembl rs2143699891
- Q7H (p.Gln7His), TOPMed rs1298821177, gnomAD rs1298821177, REVEL 0.05, CADD 31.00
- Q7P (p.Gln7Pro), TOPMed rs1440570848, gnomAD rs1440570848, REVEL 0.12, CADD 25.60
- Q7R (p.Gln7Arg), TOPMed rs1440570848, gnomAD rs1440570848
- V9I (p.Val9Ile), Ensembl rs2143697269, REVEL 0.08, CADD 10.50
- N10S (p.Asn10Ser), gnomAD rs1289313411, REVEL 0.02, CADD 20.10
- M13I (p.Met13Ile), NCI-TCGA Cosmic COSV7073, Variant assessed as somatic; moderate impact.
- M13L (p.Met13Leu), ExAC rs752723720, gnomAD rs752723720
- M13R (p.Met13Arg), Ensembl rs1197230620
- Q14* (p.Gln14Ter), Ensembl rs2143697229
- V15I (p.Val15Ile), gnomAD rs1316020312, REVEL 0.03, CADD 0.75
- N16S (p.Asn16Ser), ExAC rs756092705, gnomAD rs756092705, REVEL 0.05, CADD 9.26
- I18K (p.Ile18Lys), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- I18M (p.Ile18Met), TOPMed rs1199340896, gnomAD rs1199340896, REVEL 0.04, CADD 14.80
- K20Q (p.Lys20Gln), ESP rs369852373, ExAC rs369852373, TOPMed rs369852373, gnomAD rs369852373, REVEL 0.09, CADD 23.80
- D23H (p.Asp23His), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- A24S (p.Ala24Ser), Ensembl rs2143697146
- A24V (p.Ala24Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K25N (p.Lys25Asn), NCI-TCGA Cosmic COSV7073, Variant assessed as somatic; moderate impact.
- K26E (p.Lys26Glu), gnomAD rs1424484074, REVEL 0.12, CADD 24.60
- K26N (p.Lys26Asn), ExAC rs761604860, gnomAD rs761604860, REVEL 0.14, CADD 25.50
- S29C (p.Ser29Cys), Ensembl rs2143697082
- S29P (p.Ser29Pro), Ensembl rs2035395393, REVEL 0.38, CADD 28.50
- R32I (p.Arg32Ile), rs963352942, NCI-TCGA Cosmic COSV7073, TOPMed rs963352942, gnomAD rs963352942, REVEL 0.21, CADD 28.20, Variant assessed as somatic; moderate impact.
- Q35* (p.Gln35Ter), NCI-TCGA Cosmic COSV7073, Variant assessed as somatic; high impact.
- Q35R (p.Gln35Arg), TOPMed rs1416728144, gnomAD rs1416728144, REVEL 0.39, CADD 24.80, Uncertain significance, not specified
- T38A (p.Thr38Ala), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- T38I (p.Thr38Ile), Ensembl rs2143697035
- Q39P (p.Gln39Pro), ExAC rs773891227, TOPMed rs773891227, gnomAD rs773891227, REVEL 0.31, CADD 27.60
- E41* (p.Glu41Ter), Ensembl rs2143696987
- E41K (p.Glu41Lys), Ensembl rs2143696987
- L44V (p.Leu44Val), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- L45F (p.Leu45Phe), TOPMed rs1296708366, gnomAD rs1296708366, REVEL 0.42, CADD 29.30
- R46C (p.Arg46Cys), Ensembl rs2143696945
- R46H (p.Arg46His), Ensembl rs2143696934
- D48N (p.Asp48Asn), Ensembl rs2143696898
- G52D (p.Gly52Asp), Ensembl rs2143696891
- G52V (p.Gly52Val), Ensembl rs2143696891
- S53F (p.Ser53Phe), Ensembl rs2143696855
- S53P (p.Ser53Pro), Ensembl rs1567792188
- S53Y (p.Ser53Tyr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- E55G (p.Glu55Gly), rs549097402, ClinGen CA8543846, ClinVar RCV004468044, 1000Genomes rs549097402, REVEL 0.47, CADD 27.10, Uncertain significance, not specified
- L56* (p.Leu56Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- L56S (p.Leu56Ser), TOPMed rs1266743916, gnomAD rs1266743916, REVEL 0.10, CADD 22.60
- T58N (p.Thr58Asn), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- Q59H (p.Gln59His), Ensembl rs2143696798
- M61T (p.Met61Thr), rs187674496, ClinGen CA8543840, ClinVar RCV004186548, 1000Genomes rs187674496, REVEL 0.47, CADD 26.00, Uncertain significance, not specified
- V63I (p.Val63Ile), Ensembl rs2143696259, REVEL 0.13, CADD 22.50
- D65N (p.Asp65Asn), TOPMed rs2035392401, REVEL 0.16, CADD 25.00
- D67N (p.Asp67Asn), NCI-TCGA Cosmic COSV1013, REVEL 0.12, CADD 23.60, Variant assessed as somatic; moderate impact.
- D67V (p.Asp67Val), Ensembl rs2143696229
- D67Y (p.Asp67Tyr), NCI-TCGA Cosmic COSV1013, REVEL 0.26, CADD 25.50, Variant assessed as somatic; moderate impact.
- V68I (p.Val68Ile), ExAC rs777879639, TOPMed rs777879639, gnomAD rs777879639, REVEL 0.10, CADD 8.11
- G69C (p.Gly69Cys), ExAC rs772240354, gnomAD rs772240354, REVEL 0.38, CADD 25.40
- G69D (p.Gly69Asp), Ensembl rs2143696194, REVEL 0.32, CADD 23.90
- I70L (p.Ile70Leu), TOPMed rs1332466568
- I70V (p.Ile70Val), TOPMed rs1332466568
- Y72C (p.Tyr72Cys), TOPMed rs1019417784, gnomAD rs1019417784, REVEL 0.15, CADD 22.50
- Y72F (p.Tyr72Phe), TOPMed rs1019417784, gnomAD rs1019417784
- E74K (p.Glu74Lys), TOPMed rs1242573634
- V75I (p.Val75Ile), TOPMed rs2035391927, gnomAD rs2035391927, REVEL 0.07, CADD 16.10
- T76A (p.Thr76Ala), TOPMed rs1490438473, gnomAD rs1490438473, REVEL 0.21, CADD 24.00
- T76I (p.Thr76Ile), ESP rs373052063, ExAC rs373052063, TOPMed rs373052063, gnomAD rs373052063, REVEL 0.39, CADD 26.10
- F77Y (p.Phe77Tyr), gnomAD rs1203204555, REVEL 0.11, CADD 17.40
- G80C (p.Gly80Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D86N (p.Asp86Asn), Ensembl rs2143695982, REVEL 0.48, CADD 31.00
- E87G (p.Glu87Gly), NCI-TCGA TCGA novel, REVEL 0.76, CADD 32.00, Variant assessed as somatic; moderate impact.
- I88N (p.Ile88Asn), TOPMed rs796052143, gnomAD rs796052143, Likely benign
- I88S (p.Ile88Ser), TOPMed rs796052143, gnomAD rs796052143, REVEL 0.77, CADD 31.00, Likely benign
- I88T (p.Ile88Thr), rs796052143, ClinGen CA204067, ClinVar RCV000190129, TOPMed rs796052143, REVEL 0.75, CADD 28.40, Likely benign, Long QT syndrome
- L89I (p.Leu89Ile), NCI-TCGA Cosmic COSV7073, REVEL 0.24, CADD 24.50, Variant assessed as somatic; moderate impact.
- V90=, NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; low impact.
- A92S (p.Ala92Ser), gnomAD rs1203191432, REVEL 0.52, CADD 26.80
- A92T (p.Ala92Thr), gnomAD rs1203191432, REVEL 0.78, CADD 29.20
- A92V (p.Ala92Val), Ensembl rs2143694901, REVEL 0.69, CADD 32.00
- A93T (p.Ala93Thr), TOPMed rs1018933690, gnomAD rs1018933690, REVEL 0.48, CADD 29.10
- A93V (p.Ala93Val), Ensembl rs2035386452, REVEL 0.44, CADD 31.00
- N95T (p.Asn95Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K96N (p.Lys96Asn), Ensembl rs61054733
- K96Q (p.Lys96Gln), ExAC rs773676790, TOPMed rs773676790, gnomAD rs773676790, REVEL 0.58, CADD 29.70
- Q97K (p.Gln97Lys), Ensembl rs57842097, REVEL 0.41, CADD 24.80
- P100S (p.Pro100Ser), gnomAD rs1225618145, REVEL 0.10, CADD 22.60
- K101E (p.Lys101Glu), TOPMed rs1009430190, gnomAD rs1009430190, REVEL 0.10, CADD 24.50, Uncertain significance, not specified
- M102C (p.Met102Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- S103C (p.Ser103Cys), Ensembl rs2143694779
- S103Y (p.Ser103Tyr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- C104* (p.Cys104Ter), gnomAD rs1436802127, CADD 34.00
- I105F (p.Ile105Phe), Ensembl rs2143694751, REVEL 0.66, CADD 31.00
- R106K (p.Arg106Lys), TOPMed rs1380174914, gnomAD rs1380174914, REVEL 0.12, CADD 17.90
- R106T (p.Arg106Thr), TOPMed rs1380174914, gnomAD rs1380174914, REVEL 0.18, CADD 23.30
- V107I (p.Val107Ile), TOPMed rs1335490488, gnomAD rs1335490488, REVEL 0.06, CADD 16.10
- V107L (p.Val107Leu), TOPMed rs1335490488, gnomAD rs1335490488, REVEL 0.19, CADD 22.70, Uncertain significance, not specified
- I109V (p.Ile109Val), gnomAD rs1414600000, REVEL 0.14, CADD 22.20
- P111A (p.Pro111Ala), Ensembl rs2143694686
- P111L (p.Pro111Leu), TOPMed rs1347294511, REVEL 0.24, CADD 25.00
- E112K (p.Glu112Lys), Ensembl rs2143688150, REVEL 0.23, CADD 23.70
- I116V (p.Ile116Val), TOPMed rs1371166899, gnomAD rs1371166899, REVEL 0.12, CADD 20.80
- S117R (p.Ser117Arg), TOPMed rs1414741244, gnomAD rs1414741244, REVEL 0.38, CADD 22.70
- I118L (p.Ile118Leu), TOPMed rs2035351790, REVEL 0.19, CADD 22.90
- W119* (p.Trp119Ter), Ensembl rs2143688073, CADD 26.90
- W119C (p.Trp119Cys), Ensembl rs2143688073, REVEL 0.43, CADD 28.10
- W119S (p.Trp119Ser), Ensembl rs2143688085
- K123* (p.Lys123Ter), TOPMed rs1418769357, gnomAD rs1418769357, CADD 36.00
- G124C (p.Gly124Cys), rs2544422336, ClinGen CA399352883, ClinVar RCV004167069, REVEL 0.86, CADD 26.50, Uncertain significance, not specified
- I125V (p.Ile125Val), TOPMed rs967876210, gnomAD rs967876210, REVEL 0.40, CADD 23.50
- V127F (p.Val127Phe), Ensembl rs2143688002
- V128F (p.Val128Phe), Ensembl rs2143687994
- E129Q (p.Glu129Gln), Ensembl rs2143687980
- K131E (p.Lys131Glu), TOPMed rs930032673, gnomAD rs930032673, REVEL 0.22, CADD 25.60
- V132F (p.Val132Phe), TOPMed rs1012367614, REVEL 0.21, CADD 23.70
- V132I (p.Val132Ile), TOPMed rs1012367614
- M135I (p.Met135Ile), TOPMed rs919128157, gnomAD rs919128157, REVEL 0.08, CADD 18.50
- V137I (p.Val137Ile), Ensembl rs2143687902, REVEL 0.08, CADD 22.90
- P138L (p.Pro138Leu), Ensembl rs2143687885
- A139V (p.Ala139Val), Ensembl rs2143687874, REVEL 0.31, CADD 21.60
- L140F (p.Leu140Phe), Ensembl rs2143687863
- I141V (p.Ile141Val), Ensembl rs2035350782, REVEL 0.17, CADD 24.70, Uncertain significance, not specified
- G143V (p.Gly143Val), Ensembl rs2143687832, REVEL 0.72, CADD 26.30
- Q144H (p.Gln144His), Ensembl rs2143687820, REVEL 0.16, CADD 7.42
- T147S (p.Thr147Ser), Ensembl rs2143687783
- S149C (p.Ser149Cys), Ensembl rs2143687749
- S149N (p.Ser149Asn), gnomAD rs2035350456, REVEL 0.38, CADD 24.80
- N150K (p.Asn150Lys), Ensembl rs2143687718
- N150S (p.Asn150Ser), TOPMed rs1240257662, gnomAD rs1240257662, REVEL 0.50, CADD 25.40
- D152E (p.Asp152Glu), TOPMed rs1290529154, gnomAD rs1290529154, REVEL 0.38, CADD 23.20
- D152N (p.Asp152Asn), TOPMed rs2035350271, REVEL 0.04, CADD 22.50
- D154E (p.Asp154Glu), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- D154G (p.Asp154Gly), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- E155G (p.Glu155Gly), NCI-TCGA Cosmic COSV7073, Variant assessed as somatic; moderate impact.
- E155V (p.Glu155Val), NCI-TCGA Cosmic COSV7073, Variant assessed as somatic; moderate impact.
- K156N (p.Lys156Asn), NCI-TCGA TCGA novel, gnomAD rs1460053469, Variant assessed as somatic; moderate impact.
- K157N (p.Lys157Asn), Ensembl rs2143687638
- V158E (p.Val158Glu), Ensembl rs2143687623
- V158L (p.Val158Leu), Ensembl rs2143687628, REVEL 0.24, CADD 22.30
- R162* (p.Arg162Ter), NCI-TCGA Cosmic COSV7073, Ensembl rs2035346422, CADD 37.00, Variant assessed as somatic; high impact.
- R162G (p.Arg162Gly), Ensembl rs2035346422
- R162Q (p.Arg162Gln), Ensembl rs2143686955, REVEL 0.54, CADD 28.50
- Y165C (p.Tyr165Cys), rs2544421723, ClinGen CA399351966, ClinVar RCV004134421, REVEL 0.70, CADD 29.80, Uncertain significance, not specified
- G166E (p.Gly166Glu), gnomAD rs1203971586, REVEL 0.97, CADD 26.40
- A167D (p.Ala167Asp), Ensembl rs2143686929, REVEL 0.74, CADD 27.20
- A167V (p.Ala167Val), rs868251333, []
- N171K (p.Asn171Lys), Ensembl rs867525891, REVEL 0.65, CADD 22.60
- I172V (p.Ile172Val), Ensembl rs2035346240, REVEL 0.18, CADD 23.50
- S174N (p.Ser174Asn), Ensembl rs2143686893, REVEL 0.62, CADD 25.50
- K176R (p.Lys176Arg), gnomAD rs1329284445, REVEL 0.05, CADD 21.00
- F177C (p.Phe177Cys), NCI-TCGA Cosmic COSV1013, Variant assessed as somatic; moderate impact.
- F177I (p.Phe177Ile), Ensembl rs2035346097
- F177L (p.Phe177Leu), Ensembl rs2143686850, REVEL 0.44, CADD 24.80
- V179L (p.Val179Leu), Ensembl rs2143686831, REVEL 0.29, CADD 23.20
- E180K (p.Glu180Lys), ESP rs80184041, ExAC rs80184041, TOPMed rs80184041, gnomAD rs80184041, REVEL 0.63, CADD 26.70
- E180Q (p.Glu180Gln), ESP rs80184041, ExAC rs80184041, TOPMed rs80184041, gnomAD rs80184041, REVEL 0.38, CADD 25.70, Uncertain significance, not specified
- E180V (p.Glu180Val), 1000Genomes rs575665799, ExAC rs575665799, gnomAD rs575665799, REVEL 0.48, CADD 29.30, Uncertain significance, not specified
- T181P (p.Thr181Pro), ExAC rs774581970, gnomAD rs774581970, REVEL 0.69, CADD 26.40
- A182S (p.Ala182Ser), Ensembl rs867039956, REVEL 0.10, CADD 19.70
- A182V (p.Ala182Val), Ensembl rs868251333, REVEL 0.11, CADD 24.30
- S183N (p.Ser183Asn), Ensembl rs2143686743, REVEL 0.10, CADD 20.50
- R184G (p.Arg184Gly), ExAC rs562223504, TOPMed rs562223504, gnomAD rs562223504, REVEL 0.13, CADD 22.60, Uncertain significance, not specified
- K188R (p.Lys188Arg), gnomAD rs1456737212, REVEL 0.03, CADD 22.30
- M189I (p.Met189Ile), NCI-TCGA TCGA novel, REVEL 0.12, CADD 13.50, Variant assessed as somatic; moderate impact.
- M189K (p.Met189Lys), TOPMed rs1161521897, gnomAD rs1161521897, REVEL 0.09, CADD 19.60
- M189T (p.Met189Thr), TOPMed rs1161521897, gnomAD rs1161521897, REVEL 0.06, CADD 18.40
- F190L (p.Phe190Leu), NCI-TCGA Cosmic COSV7073, REVEL 0.18, CADD 22.80, Variant assessed as somatic; moderate impact.
- K191E (p.Lys191Glu), TOPMed rs1318467719, gnomAD rs1318467719, REVEL 0.25, CADD 24.20
- Q192H (p.Gln192His), Ensembl rs1200411904, REVEL 0.52, CADD 35.00
- W194* (p.Trp194Ter), Ensembl rs2035341946, CADD 36.00
- W194H (p.Trp194His), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- M195I (p.Met195Ile), gnomAD rs1305742480, REVEL 0.06, CADD 17.00
- M195V (p.Met195Val), Ensembl rs1598619477, REVEL 0.06, CADD 18.60
- D196G (p.Asp196Gly), gnomAD rs1271981703, REVEL 0.17, CADD 24.40
- D196H (p.Asp196His), Ensembl rs2143685965
- M198G (p.Met198Gly), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- R200G (p.Arg200Gly), TOPMed rs2035341542, REVEL 0.09, CADD 22.20
- R200S (p.Arg200Ser), Ensembl rs2143685908
Public TOP2A analysis runs
- TOP2A analysis run — TOP2A (1,866 variants) — completed 2026-08-20