SETD2 (Q9BYW2) variants and mutations
SETD2 (also known as Q9BYW2) is a human protein-coding gene encoding a histone-lysine N-methyltransferase protein. It deposits H3K36 trimethylation across actively transcribed genes and helps coordinate RNA processing, DNA repair, and genome stability. Somatic loss is common in renal and other cancers, while germline pathogenic variants can cause Luscan-Lumish overgrowth syndrome. This analysis covers 10,492 SETD2 variants and mutations. Of these, 26% have computational variant effect predictions. Disease context includes Luscan-Lumish syndrome, clear cell renal carcinoma, and pleural mesothelioma. Example SETD2 variants include M1K, M1T, and K2N.
Variant analysis overview
- Gene: SETD2
- Protein: Q9BYW2
- UniProt accession: Q9BYW2
- Organism: Homo sapiens
- Variants analyzed: 10492
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 10,382 unspecified-consequence records; 31 missense variants; 67 synonymous variants; 4 frameshift variants; 5 splice-region variants; 2 in-frame deletions; 1 substitution
- Prediction scores: 2,737 variants have prediction scores (26% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Luscan-Lumish syndrome, clear cell renal carcinoma, pleural mesothelioma, Intellectual disability, intellectual developmental disorder, autosomal dominant 70, hereditary disease, neurodegenerative disease, lung adenocarcinoma, B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, renal cell carcinoma, melanoma.
Protein structure and variant hotspots
- Protein features: 4 domains; 17 binding sites; 30 post-translational modification sites.
- Structural context: 886 variants have structural context.
- PTM context: 135 variants overlap post-translational modification sites.
- Experimental data: 49 protein positions have experimental scores. Source: SETD2 WW domain domainome 1.0.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable SETD2 variants
Examples include M1K, M1T, K2N, K2R, Q3*, Q3E, L4V, Q5*. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1K (p.Met1Lys), rs1221828308, ClinGen CA352512819, ClinVar RCV000795794, MetaLR 0.51, MetaSVM -0.34, Likely benign, Luscan-Lumish syndrome
- M1T (p.Met1Thr), rs1221828308, ClinGen CA352512823, ClinVar RCV001752042, MetaLR 0.51, MetaSVM -0.34, Uncertain significance, not provided
- K2N (p.Lys2Asn), Ensembl rs2106868731, REVEL 0.30, AlphaMissense 0.08, Uncertain significance, in ALL
- K2R (p.Lys2Arg), UniProt VAR 079054, REVEL 0.30, CADD 24.20, Uncertain significance, in ALL
- Q3* (p.Gln3Ter), TOPMed rs1410684482, gnomAD rs1410684482, CADD 35.00
- Q3E (p.Gln3Glu), TOPMed rs1410684482, gnomAD rs1410684482, REVEL 0.28, AlphaMissense 0.14, Uncertain significance, Inborn genetic diseases
- L4V (p.Leu4Val), Ensembl rs2106868717, REVEL 0.22, CADD 15.50
- Q5* (p.Gln5Ter), rs2545707347, ClinGen CA352512742, ClinVar RCV004555250, CADD 35.00, Uncertain significance
- Q5H (p.Gln5His), TOPMed rs1697587118, REVEL 0.24, CADD 22.50
- Q5R (p.Gln5Arg), Ensembl rs1575863515, REVEL 0.17, CADD 19.80
- P6L (p.Pro6Leu), ExAC rs773983305, REVEL 0.20, CADD 23.00
- Q7* (p.Gln7Ter), rs541943893, ClinGen CA2363807, ClinVar RCV000623624, ClinVar RCV000652616, CADD 35.00, Likely benign
- Q7H (p.Gln7His), Ensembl rs2106868637, REVEL 0.26, CADD 21.40
- P8L (p.Pro8Leu), TOPMed rs1382765308, REVEL 0.35, CADD 23.10
- P8S (p.Pro8Ser), Ensembl rs2106868617, REVEL 0.23, CADD 22.50
- P9L (p.Pro9Leu), rs1553707534, ClinGen CA352512636, ClinVar RCV000533340, Ensembl rs1553707534, REVEL 0.30, CADD 23.10, Uncertain significance, Luscan-Lumish syndrome
- P9S (p.Pro9Ser), TOPMed rs1244597073, gnomAD rs1244597073, REVEL 0.33, CADD 20.30
- P10L (p.Pro10Leu), rs773221585, ClinGen CA2363803, ClinVar RCV001043681, ExAC rs773221585, REVEL 0.26, CADD 21.10, Conflicting interpretations, Luscan-Lumish syndrome
- K11N (p.Lys11Asn), rs1575863434, ClinGen CA352512595, ClinVar RCV001497626, TOPMed rs1575863434, REVEL 0.25, CADD 24.70, Likely benign, Luscan-Lumish syndrome
- K11T (p.Lys11Thr), Ensembl rs868177166
- Y16F (p.Tyr16Phe), TOPMed rs1265402763, gnomAD rs1265402763, REVEL 0.30, CADD 24.20
- D17E (p.Asp17Glu), TOPMed rs1435832395, REVEL 0.26, AlphaMissense 0.10
- P18Q (p.Pro18Gln), gnomAD rs1697585520, REVEL 0.34, AlphaMissense 0.08
- E19G (p.Glu19Gly), UniProt VAR 079055, REVEL 0.27, CADD 25.30, Uncertain significance, in ALL
- H20P (p.His20Pro), Ensembl rs2106868380
- H20Y (p.His20Tyr), Ensembl rs2106868390, REVEL 0.29, CADD 23.50
- T22N (p.Thr22Asn), ExAC rs769869483, gnomAD rs769869483, REVEL 0.35, AlphaMissense 0.08
- T22P (p.Thr22Pro), Ensembl rs2106868358, REVEL 0.36, CADD 25.60
- T22S (p.Thr22Ser), Ensembl rs2106868358, REVEL 0.30, AlphaMissense 0.11
- P23L (p.Pro23Leu), TOPMed rs892374525, gnomAD rs892374525, REVEL 0.24, CADD 21.70, Uncertain significance
- P23R (p.Pro23Arg), rs892374525, ClinGen CA352512333, ClinVar RCV001066060, ClinVar RCV005051853, REVEL 0.25, AlphaMissense 0.07, Uncertain significance, SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowt
- E24G (p.Glu24Gly), TOPMed rs1181685588, gnomAD rs1181685588, REVEL 0.28, CADD 25.80
- E25* (p.Glu25Ter), NCI-TCGA Cosmic COSV1003, CADD 45.00, Variant assessed as somatic; high impact.
- E27Q (p.Glu27Gln), rs2545662505, ClinGen CA352540023, ClinVar RCV002462416, ClinVar RCV004725289, Conflicting interpretations, Luscan-Lumish syndrome; Intellectual developmental disorder, autosomal dominant
- A30P (p.Ala30Pro), Ensembl rs2106730333
- A30S (p.Ala30Ser), Ensembl rs2106730333
- A30T (p.Ala30Thr), Ensembl rs2106730333
- K31* (p.Lys31Ter), TOPMed rs919876748
- K31E (p.Lys31Glu), TOPMed rs919876748, REVEL 0.45, CADD 26.80
- K31M (p.Lys31Met), Ensembl rs2106730263
- K31N (p.Lys31Asn), rs2106730247, ClinGen CA352538622, ClinVar RCV001814728, Ensembl rs2106730247, REVEL 0.34, CADD 23.50, Uncertain significance, not provided
- K31R (p.Lys31Arg), Ensembl rs2106730263
- K31T (p.Lys31Thr), Ensembl rs2106730263
- I32F (p.Ile32Phe), TOPMed rs1170321784, gnomAD rs1170321784, Uncertain significance
- I32N (p.Ile32Asn), Ensembl rs2106730201
- I32S (p.Ile32Ser), Ensembl rs2106730201
- I32T (p.Ile32Thr), Ensembl rs2106730201
- I32V (p.Ile32Val), rs1170321784, ClinGen CA352538620, ClinVar RCV000702395, TOPMed rs1170321784, REVEL 0.18, CADD 17.80, Uncertain significance, Luscan-Lumish syndrome
- E33* (p.Glu33Ter), Ensembl rs2106730167
- E33D (p.Glu33Asp), Ensembl rs2106730121
- E33G (p.Glu33Gly), Ensembl rs2106730147
- E33V (p.Glu33Val), Ensembl rs2106730147
- N34H (p.Asn34His), gnomAD rs1244194839
- N34I (p.Asn34Ile), Ensembl rs2106730088
- N34K (p.Asn34Lys), Ensembl rs2106730072
- N34S (p.Asn34Ser), Ensembl rs2106730088, REVEL 0.25, CADD 18.10
- N34Y (p.Asn34Tyr), gnomAD rs1244194839
- V35E (p.Val35Glu), Ensembl rs2106730018
- V35G (p.Val35Gly), Ensembl rs2106730018
- V35L (p.Val35Leu), gnomAD rs868820087, REVEL 0.20, CADD 19.20
- V35M (p.Val35Met), gnomAD rs868820087, REVEL 0.33, CADD 24.20, Uncertain significance, not specified
- Q36* (p.Gln36Ter), Ensembl rs2106729979
- Q36E (p.Gln36Glu), Ensembl rs2106729979
- Q36H (p.Gln36His), Ensembl rs2106729940
- Q36L (p.Gln36Leu), gnomAD rs1442368577, REVEL 0.40, CADD 23.10
- Q36R (p.Gln36Arg), gnomAD rs1442368577, REVEL 0.26, CADD 22.80
- K37* (p.Lys37Ter), Ensembl rs2106729920
- K37I (p.Lys37Ile), Ensembl rs2106729904
- K37N (p.Lys37Asn), Ensembl rs2106729878
- T38A (p.Thr38Ala), Ensembl rs2106729838, REVEL 0.17, CADD 13.10
- T38S (p.Thr38Ser), Ensembl rs2106729838
- G39A (p.Gly39Ala), TOPMed rs1452927592
- G39C (p.Gly39Cys), Ensembl rs2106729797
- G39D (p.Gly39Asp), TOPMed rs1452927592
- G39R (p.Gly39Arg), Ensembl rs2106729797
- G39S (p.Gly39Ser), Ensembl rs2106729797
- G39V (p.Gly39Val), TOPMed rs1452927592
- F40I (p.Phe40Ile), Ensembl rs2106729745
- F40L (p.Phe40Leu), Ensembl rs2106729745
- F40S (p.Phe40Ser), Ensembl rs2106729722
- F40Y (p.Phe40Tyr), Ensembl rs2106729722
- I41F (p.Ile41Phe), Ensembl rs2043248331
- I41N (p.Ile41Asn), Ensembl rs2106729674
- I41S (p.Ile41Ser), Ensembl rs2106729674
- I41T (p.Ile41Thr), Ensembl rs2106729674, REVEL 0.50, CADD 24.50
- K42* (p.Lys42Ter), Ensembl rs2106729653
- K42I (p.Lys42Ile), Ensembl rs2106729630
- K42N (p.Lys42Asn), Ensembl rs2106729608
- K42R (p.Lys42Arg), Ensembl rs2106729630
- G43A (p.Gly43Ala), Ensembl rs2106729549
- G43E (p.Gly43Glu), Ensembl rs2106729549
- G43R (p.Gly43Arg), Ensembl rs2106729585
- G43V (p.Gly43Val), Ensembl rs2106729549
- P44A (p.Pro44Ala), TOPMed rs1257544813, gnomAD rs1257544813
- P44L (p.Pro44Leu), TOPMed rs1311481935, gnomAD rs1311481935, REVEL 0.62, CADD 21.70
- P44Q (p.Pro44Gln), TOPMed rs1311481935, gnomAD rs1311481935
- P44R (p.Pro44Arg), TOPMed rs1311481935, gnomAD rs1311481935
- P44S (p.Pro44Ser), TOPMed rs1257544813, gnomAD rs1257544813, REVEL 0.48, CADD 22.60
- P44T (p.Pro44Thr), TOPMed rs1257544813, gnomAD rs1257544813
- M45I (p.Met45Ile), Ensembl rs2106729394
- M45K (p.Met45Lys), ExAC rs753767436, gnomAD rs753767436
- M45L (p.Met45Leu), 1000Genomes rs568718208, ExAC rs568718208, TOPMed rs568718208, gnomAD rs568718208, Uncertain significance
- M45R (p.Met45Arg), ExAC rs753767436, gnomAD rs753767436
- M45T (p.Met45Thr), ExAC rs753767436, gnomAD rs753767436
- M45V (p.Met45Val), rs568718208, ClinGen CA2363763, ClinVar RCV002942320, 1000Genomes rs568718208, AlphaMissense 0.09, MetaLR 0.35, Uncertain significance, Luscan-Lumish syndrome
- F46* (p.Phe46Ter), ExAC rs754023019, gnomAD rs754023019
- F46C (p.Phe46Cys), Ensembl rs2106729329
- F46I (p.Phe46Ile), ExAC rs763941922, TOPMed rs763941922, gnomAD rs763941922, REVEL 0.38, CADD 23.20
- F46L (p.Phe46Leu), TOPMed rs1251864755, gnomAD rs1251864755, REVEL 0.35, CADD 17.70
- F46V (p.Phe46Val), ExAC rs763941922, TOPMed rs763941922, gnomAD rs763941922
- F46Y (p.Phe46Tyr), Ensembl rs2106729329
- K47* (p.Lys47Ter), Ensembl rs2106729291
- K47I (p.Lys47Ile), Ensembl rs1317192082
- K47N (p.Lys47Asn), Ensembl rs2106729247
- K47R (p.Lys47Arg), Ensembl rs1317192082
- G48A (p.Gly48Ala), ExAC rs760120112, TOPMed rs760120112, gnomAD rs760120112, Uncertain significance
- G48C (p.Gly48Cys), Ensembl rs2106729214
- G48D (p.Gly48Asp), rs760120112, ClinGen CA2363759, ClinVar RCV004455516, ExAC rs760120112, REVEL 0.51, CADD 24.50, Uncertain significance, Inborn genetic diseases
- G48R (p.Gly48Arg), Ensembl rs2106729214
- G48S (p.Gly48Ser), Ensembl rs2106729214
- G48V (p.Gly48Val), ExAC rs760120112, TOPMed rs760120112, gnomAD rs760120112, Uncertain significance
- V49D (p.Val49Asp), Ensembl rs2106729109
- V49F (p.Val49Phe), Ensembl rs2106729139
- V49G (p.Val49Gly), Ensembl rs2106729109
- V49I (p.Val49Ile), NCI-TCGA Cosmic COSV5743, Ensembl rs2106729139, Uncertain significance, not specified
- V49L (p.Val49Leu), Ensembl rs2106729139
- A50D (p.Ala50Asp), TOPMed rs2043246649, gnomAD rs2043246649, REVEL 0.41, CADD 25.50
- A50G (p.Ala50Gly), TOPMed rs2043246649, gnomAD rs2043246649, REVEL 0.29, CADD 25.00
- A50P (p.Ala50Pro), 1000Genomes rs191985301, TOPMed rs191985301, gnomAD rs191985301, Likely benign
- A50S (p.Ala50Ser), 1000Genomes rs191985301, TOPMed rs191985301, gnomAD rs191985301, Likely benign
- A50T (p.Ala50Thr), rs191985301, ClinGen CA73812492, ClinVar RCV000652628, ClinVar RCV004533419, REVEL 0.28, CADD 24.50, Conflicting interpretations, Luscan-Lumish syndrome
- A50V (p.Ala50Val), TOPMed rs2043246649, gnomAD rs2043246649, REVEL 0.31, CADD 25.10
- S51C (p.Ser51Cys), Ensembl rs2106728940, Uncertain significance, not provided; not specified
- S51F (p.Ser51Phe), Ensembl rs2106728940
- S51P (p.Ser51Pro), Ensembl rs2106728963
- S51T (p.Ser51Thr), Ensembl rs2106728963
- S52I (p.Ser52Ile), Ensembl rs2106728900
- S52N (p.Ser52Asn), Ensembl rs2106728900
- S52R (p.Ser52Arg), Ensembl rs2106728880
- S52T (p.Ser52Thr), Ensembl rs2106728900
- R53* (p.Arg53Ter), TOPMed rs1461772708, gnomAD rs1461772708, CADD 34.00
- R53G (p.Arg53Gly), TOPMed rs1461772708, gnomAD rs1461772708
- R53L (p.Arg53Leu), TOPMed rs745499104, gnomAD rs745499104, Uncertain significance
- R53P (p.Arg53Pro), TOPMed rs745499104, gnomAD rs745499104, Uncertain significance
- R53Q (p.Arg53Gln), rs745499104, ClinGen CA73812486, ClinVar RCV001296867, TOPMed rs745499104, REVEL 0.32, CADD 25.50, Uncertain significance, Luscan-Lumish syndrome
- F54C (p.Phe54Cys), rs2043245978, ClinVar RCV004586093, TOPMed rs2043245978, AlphaMissense 1.00, MetaLR 0.73, Uncertain significance, not specified
- F54I (p.Phe54Ile), Ensembl rs2106728793
- F54L (p.Phe54Leu), Ensembl rs2106728793, REVEL 0.40, CADD 22.60
- F54S (p.Phe54Ser), TOPMed rs2043245978, Uncertain significance
- F54V (p.Phe54Val), Ensembl rs2106728793
- L55* (p.Leu55Ter), Ensembl rs2106728715
- L55F (p.Leu55Phe), rs2545655870, ClinGen CA352538371, ClinVar RCV002836829, Uncertain significance, Inborn genetic diseases
- L55M (p.Leu55Met), TOPMed rs2043245846
- L55S (p.Leu55Ser), Ensembl rs2106728715
- P56A (p.Pro56Ala), Ensembl rs2106728693
- P56H (p.Pro56His), Ensembl rs2043245677
- P56L (p.Pro56Leu), Ensembl rs2043245677
- P56R (p.Pro56Arg), Ensembl rs2043245677, REVEL 0.58, CADD 25.70
- P56T (p.Pro56Thr), Ensembl rs2106728693
- K57I (p.Lys57Ile), Ensembl rs2106728625
- K57N (p.Lys57Asn), Ensembl rs2106728591
- K57R (p.Lys57Arg), rs2106728625, ClinGen CA352538358, ClinVar RCV003127361, REVEL 0.40, CADD 24.30, Likely benign, Autism spectrum disorder
- G58A (p.Gly58Ala), Ensembl rs2043245559, Uncertain significance
- G58D (p.Gly58Asp), Ensembl rs2043245559, Uncertain significance
- G58V (p.Gly58Val), rs2043245559, ClinGen CA352538347, ClinVar RCV001528139, Ensembl rs2043245559, AlphaMissense 0.96, MetaLR 0.93, Uncertain significance, Luscan-Lumish syndrome
- T59I (p.Thr59Ile), Ensembl rs2106728498
- T59N (p.Thr59Asn), Ensembl rs2106728498, REVEL 0.35, CADD 23.10
- T59P (p.Thr59Pro), Ensembl rs2106728527
- T59S (p.Thr59Ser), Ensembl rs2106728498
- K60I (p.Lys60Ile), gnomAD rs1340972697
- K60N (p.Lys60Asn), Ensembl rs2106728415
- K60R (p.Lys60Arg), gnomAD rs1340972697, REVEL 0.39, CADD 22.40
- T61S (p.Thr61Ser), Ensembl rs2106728384
- K62E (p.Lys62Glu), gnomAD rs1454647589, REVEL 0.65, CADD 25.90
- K62N (p.Lys62Asn), Ensembl rs2106728332
- V63D (p.Val63Asp), Ensembl rs2106728293
- V63I (p.Val63Ile), gnomAD rs1398215878, REVEL 0.40, CADD 24.40
- V63L (p.Val63Leu), gnomAD rs1398215878
- N64I (p.Asn64Ile), Ensembl rs2106728236
- N64K (p.Asn64Lys), Ensembl rs2106728209
Public SETD2 analysis runs
- SETD2 analysis run — SETD2 (10,492 variants) — completed 2026-08-18