KMT2A (Q03164) variants and mutations
KMT2A (also known as Q03164) is a human protein-coding gene encoding a histone-lysine N-methyltransferase 2A protein. It maintains transcription of developmental and hematopoietic genes through chromatin-regulatory complexes and H3K4 methylation. Rearrangements create potent fusion oncoproteins that drive acute leukemias, while germline loss-of-function variants cause Wiedemann-Steiner syndrome. This analysis covers 7,780 KMT2A variants and mutations. Of these, 42% have computational variant effect predictions. Disease context includes Wiedemann-Steiner syndrome, hereditary disease, and Intellectual disability. Example KMT2A variants include M1L, A2V, and A2T.
Variant analysis overview
- Gene: KMT2A
- Protein: Q03164
- UniProt accession: Q03164
- Organism: Homo sapiens
- Variants analyzed: 7780
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 7,368 unspecified-consequence records; 234 missense variants; 129 synonymous variants; 9 stop-gained variants; 15 in-frame deletions; 19 frameshift variants; 3 in-frame insertions; 1 splice-region variants; 2 substitution
- Prediction scores: 3,277 variants have prediction scores (42% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Wiedemann-Steiner syndrome, hereditary disease, Intellectual disability, acute myeloid leukemia, acute lymphoblastic leukemia, Kabuki syndrome 1, urinary bladder cancer, microcephaly, Rare genetic intellectual disability, melanoma, neurodevelopmental disorder, B-cell acute lymphoblastic leukemia.
Protein structure and variant hotspots
- Protein features: 5 domains; 17 binding sites; 33 post-translational modification sites.
- Structural context: 699 variants have structural context.
- PTM context: 68 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable KMT2A variants
Examples include M1L, A2V, A2T, A2S, A2G, A2E, A2A, H3P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1L (p.Met1Leu), rs2497095341, ClinGen CA382796613, ClinVar RCV003133899, Uncertain significance, Wiedemann-Steiner syndrome
- A2V (p.Ala2Val), TOPMed rs1241117548, REVEL 0.34, MetaLR 0.46
- A2T (p.Ala2Thr), gnomAD 11-118436516-G-A, REVEL 0.39, CADD 25.50
- A2S (p.Ala2Ser), gnomAD 11-118436516-G-T, REVEL 0.35, CADD 24.80
- A2G (p.Ala2Gly), gnomAD 11-118436517-C-G, REVEL 0.33, CADD 24.60
- A2E (p.Ala2Glu), gnomAD 11-118436517-C-A, REVEL 0.33, CADD 24.40
- A2A (p.Ala2Ala), gnomAD 11-118436518-G-A, CADD 15.20
- H3P (p.His3Pro), Ensembl rs2134151844, MetaLR 0.30, MetaSVM -0.67
- H3Y (p.His3Tyr), gnomAD 11-118436519-C-T, REVEL 0.19, CADD 22.50
- H3N (p.His3Asn), gnomAD 11-118436519-C-A, REVEL 0.19, CADD 22.50
- H3R (p.His3Arg), gnomAD 11-118436520-A-G, REVEL 0.19, CADD 23.00
- H3L (p.His3Leu), gnomAD 11-118436520-A-T, REVEL 0.33, CADD 23.30
- H3Q (p.His3Gln), gnomAD 11-118436521-C-A, REVEL 0.23, CADD 23.00
- H3H (p.His3His), rs1949182890, gnomAD 11-118436521-C-T, CADD 13.80
- S4N (p.Ser4Asn), Ensembl rs2134151859, REVEL 0.27, MetaLR 0.33
- S4R (p.Ser4Arg), cosmic curated COSV63294, 1000Genomes rs1555138445, gnomAD rs1555138445, REVEL 0.49, MetaLR 0.38
- S4G (p.Ser4Gly), gnomAD 11-118436522-A-G, REVEL 0.31, CADD 23.40
- S4T (p.Ser4Thr), gnomAD 11-118436523-G-C, REVEL 0.33, CADD 23.20
- S4I (p.Ser4Ile), gnomAD 11-118436523-G-T, REVEL 0.53, CADD 23.90
- S4S (p.Ser4Ser), gnomAD 11-118436524-C-T, CADD 15.40
- C5S (p.Cys5Ser), rs1336274284, ClinGen CA382796670, ClinVar RCV001774427, TOPMed rs1336274284, REVEL 0.49, MetaLR 0.48, Uncertain significance, not provided
- C5R (p.Cys5Arg), gnomAD 11-118436525-T-C, REVEL 0.58, CADD 27.20
- C5F (p.Cys5Phe), gnomAD 11-118436526-G-T, REVEL 0.59, CADD 26.80
- C5Y (p.Cys5Tyr), gnomAD 11-118436526-G-A, REVEL 0.59, CADD 26.50
- C5* (p.Cys5Ter), gnomAD 11-118436527-T-A, CADD 35.00
- C5C (p.Cys5Cys), rs1949183118, gnomAD 11-118436527-T-C, CADD 16.30
- R6W (p.Arg6Trp), cosmic curated COSV63281, gnomAD rs1555138451, REVEL 0.60, MetaLR 0.48
- R6R (p.Arg6Arg), gnomAD 11-118436528-C-A, CADD 15.50
- R6Q (p.Arg6Gln), gnomAD 11-118436529-G-A, REVEL 0.41, CADD 24.30
- R6L (p.Arg6Leu), gnomAD 11-118436529-G-T, REVEL 0.55, CADD 24.20
- W7G (p.Trp7Gly), Ensembl rs2134151920, REVEL 0.59, MetaLR 0.45
- W7R (p.Trp7Arg), gnomAD 11-118436531-T-A, REVEL 0.60, CADD 27.60
- p.Trp7 Arg8delinsCys, gnomAD 11-118436531-TGGC, CADD 20.80
- W7L (p.Trp7Leu), gnomAD 11-118436532-G-T, REVEL 0.56, CADD 27.20
- W7* (p.Trp7Ter), gnomAD 11-118436532-G-A, CADD 36.00
- W7C (p.Trp7Cys), gnomAD 11-118436533-G-T, REVEL 0.59, CADD 28.80
- R8C (p.Arg8Cys), Ensembl rs2134151935, REVEL 0.49, MetaLR 0.42
- R8H (p.Arg8His), Ensembl rs2134151947, REVEL 0.23, MetaLR 0.33
- R8P (p.Arg8Pro), NCI-TCGA TCGA novel, MetaLR 0.32, MetaSVM -0.65, Variant assessed as somatic; high impact.
- R8S (p.Arg8Ser), gnomAD 11-118436534-C-A, REVEL 0.41, CADD 23.50
- R8G (p.Arg8Gly), gnomAD 11-118436534-C-G, REVEL 0.44, CADD 23.90
- R8L (p.Arg8Leu), gnomAD 11-118436535-G-T, REVEL 0.42, CADD 23.60
- R8R (p.Arg8Arg), gnomAD 11-118436536-C-T, CADD 15.30
- F9C (p.Phe9Cys), cosmic curated COSV63291, MetaLR 0.34, MetaSVM -0.51, Likely pathogenic, KMT2A-related disorder
- F9I (p.Phe9Ile), Ensembl rs2134151964, REVEL 0.43, MetaLR 0.35
- F9L (p.Phe9Leu), cosmic curated COSV63292, Ensembl rs2134151964, REVEL 0.40, MetaLR 0.35, Uncertain significance, Inborn genetic diseases
- F9S (p.Phe9Ser), Ensembl rs2134151980, REVEL 0.48, MetaLR 0.32
- F9V (p.Phe9Val), Ensembl rs2134151964, REVEL 0.46, MetaLR 0.33
- F9F (p.Phe9Phe), rs782207243, gnomAD 11-118436539-C-T, CADD 15.60
- P10H (p.Pro10His), Ensembl rs868932850, REVEL 0.57, MetaLR 0.58
- P10L (p.Pro10Leu), cosmic curated COSV63286, REVEL 0.61, MetaLR 0.52
- P10S (p.Pro10Ser), NCI-TCGA TCGA novel, REVEL 0.56, MetaLR 0.49, Variant assessed as somatic; moderate impact.
- P10T (p.Pro10Thr), gnomAD 11-118436540-C-A, REVEL 0.57, CADD 24.90
- P10P (p.Pro10Pro), rs1555138465, gnomAD 11-118436542-C-A, CADD 15.20
- A11G (p.Ala11Gly), gnomAD rs1555138467, REVEL 0.27, MetaLR 0.38
- A11P (p.Ala11Pro), Ensembl rs2134152030, MetaLR 0.33, MetaSVM -0.54, Uncertain significance
- A11T (p.Ala11Thr), rs2134152030, ClinGen CA382796786, ClinVar RCV003148511, Ensembl rs2134152030, REVEL 0.19, MetaLR 0.33, Uncertain significance, Wiedemann-Steiner syndrome
- A11S (p.Ala11Ser), gnomAD 11-118436543-G-T, REVEL 0.19, CADD 23.40
- A11V (p.Ala11Val), gnomAD 11-118436544-C-T, REVEL 0.36, CADD 23.50
- A11D (p.Ala11Asp), gnomAD 11-118436544-C-A, REVEL 0.43, CADD 23.50
- A11A (p.Ala11Ala), gnomAD 11-118436545-C-G, CADD 15.60
- R12* (p.Arg12Ter), cosmic curated COSV63283, CADD 35.00
- R12L (p.Arg12Leu), cosmic curated COSV63288, gnomAD rs1555138470, REVEL 0.58, MetaLR 0.55
- R12R (p.Arg12Arg), gnomAD 11-118436546-C-A, CADD 15.20
- R12Q (p.Arg12Gln), gnomAD 11-118436547-G-A, REVEL 0.41, CADD 27.30
- P13H (p.Pro13His), cosmic curated COSV10591, REVEL 0.36, MetaLR 0.48, Uncertain significance, not provided
- P13L (p.Pro13Leu), cosmic curated COSV63294, REVEL 0.29, MetaLR 0.31
- P13S (p.Pro13Ser), Ensembl rs2134152094, REVEL 0.27, MetaLR 0.33
- P13T (p.Pro13Thr), gnomAD 11-118436549-C-A, REVEL 0.23, CADD 22.60
- P13P (p.Pro13Pro), rs1555138474, gnomAD 11-118436551-C-T, CADD 15.30
- G14W (p.Gly14Trp), cosmic curated COSV10591, REVEL 0.47, MetaLR 0.54
- G14R (p.Gly14Arg), gnomAD 11-118436552-G-A, REVEL 0.44, CADD 25.60
- G14V (p.Gly14Val), gnomAD 11-118436553-G-T, REVEL 0.47, CADD 23.60
- G14E (p.Gly14Glu), gnomAD 11-118436553-G-A, REVEL 0.42, MetaLR 0.49
- G14G (p.Gly14Gly), rs1949183761, gnomAD 11-118436554-G-C, CADD 14.30
- T15A (p.Thr15Ala), Ensembl rs2134152130
- T15P (p.Thr15Pro), Ensembl rs2134152130, MetaLR 0.22, MetaSVM -0.77
- T15S (p.Thr15Ser), gnomAD 11-118436555-A-T, REVEL 0.14, MetaLR 0.23
- T15N (p.Thr15Asn), gnomAD 11-118436556-C-A, REVEL 0.17, MetaLR 0.25
- T15I (p.Thr15Ile), gnomAD 11-118436556-C-T, REVEL 0.12, MetaLR 0.30
- T15T (p.Thr15Thr), gnomAD 11-118436557-C-G, CADD 14.70
- T16P (p.Thr16Pro), Ensembl rs2134152157, REVEL 0.18, MetaLR 0.20
- T16S (p.Thr16Ser), gnomAD 11-118436558-A-T, REVEL 0.09, MetaLR 0.19
- T16A (p.Thr16Ala), gnomAD 11-118436558-A-G, REVEL 0.13, MetaLR 0.26
- T16N (p.Thr16Asn), gnomAD 11-118436559-C-A, REVEL 0.17, MetaLR 0.25
- T16I (p.Thr16Ile), gnomAD 11-118436559-C-T, REVEL 0.16, MetaLR 0.27
- T16T (p.Thr16Thr), rs1949183830, gnomAD 11-118436560-C-G, CADD 14.80
- G17R (p.Gly17Arg), Ensembl rs2134152181, REVEL 0.18, MetaLR 0.28
- G17W (p.Gly17Trp), gnomAD 11-118436561-G-T, REVEL 0.25, MetaLR 0.38
- G17E (p.Gly17Glu), gnomAD 11-118436562-G-A, REVEL 0.26, MetaLR 0.30
- G17V (p.Gly17Val), gnomAD 11-118436562-G-T, REVEL 0.24, MetaLR 0.31
- G17G (p.Gly17Gly), gnomAD 11-118436563-G-C, CADD 14.70
- G18C (p.Gly18Cys), Ensembl rs1555138476, REVEL 0.21, MetaLR 0.32
- G18A (p.Gly18Ala), gnomAD 11-118436560-CG-C, CADD 26.00
- G18S (p.Gly18Ser), gnomAD 11-118436564-G-A, REVEL 0.20, MetaLR 0.24
- G18V (p.Gly18Val), gnomAD 11-118436565-G-T, REVEL 0.14, MetaLR 0.32
- G18G (p.Gly18Gly), rs1367152331, gnomAD 11-118436566-C-T, CADD 15.00
- G19C (p.Gly19Cys), Ensembl rs1949184248, REVEL 0.21, MetaLR 0.30
- G19A (p.Gly19Ala), gnomAD 11-118436565-GC-G, CADD 25.10
- G19R (p.Gly19Arg), gnomAD 11-118436566-CGG-, CADD 25.20
- G19S (p.Gly19Ser), gnomAD 11-118436567-G-A, REVEL 0.13, MetaLR 0.16
- G19D (p.Gly19Asp), gnomAD 11-118436568-G-A, REVEL 0.25, MetaLR 0.27
- G19V (p.Gly19Val), gnomAD 11-118436568-G-T, REVEL 0.26, MetaLR 0.33
- G19G (p.Gly19Gly), gnomAD 11-118436569-C-A, CADD 13.70
- G20S (p.Gly20Ser), rs1305215954, ClinGen CA382796940, ClinVar RCV001932893, TOPMed rs1305215954, REVEL 0.18, MetaLR 0.35, Uncertain significance, not provided
- G20C (p.Gly20Cys), gnomAD 11-118436570-G-T, REVEL 0.31, MetaLR 0.35
- G20V (p.Gly20Val), gnomAD 11-118436571-G-T, REVEL 0.23, MetaLR 0.34
- G20D (p.Gly20Asp), gnomAD 11-118436571-G-A, REVEL 0.29, MetaLR 0.32
- G20G (p.Gly20Gly), rs1555138483, gnomAD 11-118436572-C-T, CADD 14.60
- p.Gly21 Gly23del, rs1407741917, gnomAD 11-118436563-GGGC, CADD 20.50
- G21C (p.Gly21Cys), gnomAD 11-118436573-G-T, REVEL 0.32, MetaLR 0.42
- G21R (p.Gly21Arg), gnomAD 11-118436573-G-C, REVEL 0.33, MetaLR 0.37
- G21S (p.Gly21Ser), gnomAD 11-118436573-G-A, REVEL 0.16, MetaLR 0.28
- G21V (p.Gly21Val), gnomAD 11-118436574-G-T, REVEL 0.28, MetaLR 0.30
- G21D (p.Gly21Asp), gnomAD 11-118436574-G-A, REVEL 0.30, MetaLR 0.31
- G21G (p.Gly21Gly), gnomAD 11-118436575-C-G, CADD 14.10
- G22A (p.Gly22Ala), rs1555138487, ClinGen CA382796995, ClinVar RCV003398161, ClinVar RCV004985357, REVEL 0.10, MetaLR 0.31, Uncertain significance, not provided; Inborn genetic diseases
- G22E (p.Gly22Glu), cosmic curated COSV10062, MetaLR 0.28, MetaSVM -0.62
- p.Gly22 Gly23del, gnomAD 11-118436559-CCGG, CADD 20.90
- G22R (p.Gly22Arg), gnomAD 11-118436572-C-CG, CADD 25.70
- G22W (p.Gly22Trp), gnomAD 11-118436576-G-T, REVEL 0.26, MetaLR 0.45
- G22V (p.Gly22Val), gnomAD 11-118436577-G-T, REVEL 0.26, MetaLR 0.26
- G22G (p.Gly22Gly), gnomAD 11-118436578-G-A, CADD 14.60
- p.Gly23dup, rs782302713, gnomAD 11-118436563-G-GG, CADD 20.50
- G23del (p.Gly23del), rs1407741917, gnomAD 11-118436563-GGGC, CADD 20.20
- G23A (p.Gly23Ala), gnomAD 11-118436573-GGC-, CADD 25.20
- G23R (p.Gly23Arg), gnomAD 11-118436579-G-A, REVEL 0.09, MetaLR 0.24
- G23W (p.Gly23Trp), gnomAD 11-118436579-G-T, REVEL 0.18, MetaLR 0.34
- G23E (p.Gly23Glu), gnomAD 11-118436580-G-A, REVEL 0.07, MetaLR 0.32
- G23V (p.Gly23Val), gnomAD 11-118436580-G-T, REVEL 0.12, MetaLR 0.28
- G23G (p.Gly23Gly), rs782345654, gnomAD 11-118436581-G-A, CADD 12.30
- R24G (p.Arg24Gly), Ensembl rs2134152345
- R24H (p.Arg24His), Ensembl rs2134152357, REVEL 0.27, MetaLR 0.42
- R24P (p.Arg24Pro), Ensembl rs2134152357, MetaLR 0.43, MetaSVM -0.09
- R24A (p.Arg24Ala), gnomAD 11-118436574-GC-G, CADD 23.50
- R24S (p.Arg24Ser), gnomAD 11-118436582-C-A, REVEL 0.15, MetaLR 0.28
- R24C (p.Arg24Cys), gnomAD 11-118436582-C-T, REVEL 0.13, MetaLR 0.35
- R24L (p.Arg24Leu), gnomAD 11-118436583-G-T, REVEL 0.20, MetaLR 0.31
- R24R (p.Arg24Arg), gnomAD 11-118436584-C-T, CADD 13.30
- R25G (p.Arg25Gly), Ensembl rs2134152379
- R25L (p.Arg25Leu), Ensembl rs2134152398, MetaLR 0.23, MetaSVM -0.88
- R25P (p.Arg25Pro), Ensembl rs2134152398, REVEL 0.08, MetaLR 0.24
- R25Q (p.Arg25Gln), Ensembl rs2134152398, REVEL 0.04, MetaLR 0.22
- R25W (p.Arg25Trp), cosmic curated COSV63292, REVEL 0.12, MetaLR 0.33
- R25R (p.Arg25Arg), gnomAD 11-118436587-G-T, CADD 13.50
- G26R (p.Gly26Arg), Ensembl rs2134152411, MetaLR 0.40, MetaSVM -0.32
- G26A (p.Gly26Ala), gnomAD 11-118436585-CG-C, CADD 23.50
- G26C (p.Gly26Cys), gnomAD 11-118436588-G-T, REVEL 0.41, MetaLR 0.49
- G26S (p.Gly26Ser), gnomAD 11-118436588-G-A, REVEL 0.24, MetaLR 0.33
- G26D (p.Gly26Asp), gnomAD 11-118436589-G-A, REVEL 0.28, MetaLR 0.39
- G26V (p.Gly26Val), gnomAD 11-118436589-G-T, REVEL 0.38, MetaLR 0.36
- G26G (p.Gly26Gly), rs781973852, gnomAD 11-118436590-C-T, CADD 13.80
- L27P (p.Leu27Pro), Ensembl rs2134152430, REVEL 0.31, MetaLR 0.49
- L27R (p.Leu27Arg), Ensembl rs2134152430, REVEL 0.24, MetaLR 0.49
- L27I (p.Leu27Ile), gnomAD 11-118436591-C-A, REVEL 0.07, MetaLR 0.31
- L27L (p.Leu27Leu), gnomAD 11-118436591-C-T, CADD 12.40
- G28R (p.Gly28Arg), rs782113710, ClinGen CA382797077, ClinVar RCV003558108, AlphaMissense 0.77, MetaLR 0.28, Uncertain significance, not provided
- G28W (p.Gly28Trp), rs782113710, ClinGen CA6303192, ClinVar RCV001902146, ClinVar RCV003388056, REVEL 0.11, AlphaMissense 0.77, Uncertain significance, not specified; not provided
- G28G (p.Gly28Gly), gnomAD 11-118436596-G-T, CADD 13.10
- G29C (p.Gly29Cys), rs1161519468, ClinGen CA382797098, ClinVar RCV003670985, REVEL 0.22, MetaLR 0.45, Uncertain significance, not provided
- G29S (p.Gly29Ser), TOPMed rs1161519468, REVEL 0.14, MetaLR 0.30
- G29V (p.Gly29Val), TOPMed rs1949184877, REVEL 0.21, MetaLR 0.26
- G29A (p.Gly29Ala), gnomAD 11-118436593-AG-A, CADD 23.10
- G29R (p.Gly29Arg), gnomAD 11-118436593-AGG-, CADD 23.80
- G29D (p.Gly29Asp), gnomAD 11-118436598-G-A, REVEL 0.19, MetaLR 0.38
- G29G (p.Gly29Gly), rs2134152482, gnomAD 11-118436599-C-T, CADD 14.00
- A30G (p.Ala30Gly), rs9332745, ClinGen CA172406, ClinVar RCV000146147, ClinVar RCV000442939, REVEL 0.17, MetaLR 0.14, Benign/Likely benign, not specified; not provided
- A30T (p.Ala30Thr), Ensembl rs2134152494, REVEL 0.15, MetaLR 0.42
- A30V (p.Ala30Val), rs9332745, ClinGen CA382797126, ClinVar RCV001961433, 1000Genomes rs9332745, REVEL 0.17, MetaLR 0.41, Uncertain significance, not provided
- A30R (p.Ala30Arg), gnomAD 11-118436593-A-AG, CADD 23.40
- A30S (p.Ala30Ser), gnomAD 11-118436600-G-T, REVEL 0.13, MetaLR 0.44
- A30D (p.Ala30Asp), gnomAD 11-118436601-C-A, REVEL 0.21, MetaLR 0.47
- P31S (p.Pro31Ser), TOPMed rs1413307562, MetaLR 0.28, MetaSVM -0.79
- P31R (p.Pro31Arg), gnomAD 11-118436600-GC-G, CADD 24.20
- P31T (p.Pro31Thr), gnomAD 11-118436603-C-A, REVEL 0.10, MetaLR 0.28
- P31L (p.Pro31Leu), gnomAD 11-118436604-C-T, REVEL 0.09, MetaLR 0.30
- P31Q (p.Pro31Gln), gnomAD 11-118436604-C-A, REVEL 0.11, MetaLR 0.25
- P31P (p.Pro31Pro), gnomAD 11-118436605-G-T, CADD 14.40
- R32G (p.Arg32Gly), gnomAD 11-118436606-C-G, REVEL 0.07, MetaLR 0.28
- R32W (p.Arg32Trp), gnomAD 11-118436606-C-T, REVEL 0.14, MetaLR 0.31
Public KMT2A analysis runs
- KMT2A analysis run — KMT2A (7,780 variants) — completed 2026-08-18