KMT2A

Chr 11AD

lysine methyltransferase 2A

Also known as: ALL-1, ALL1, CXXC7, GAS7, HRX, HTRX, HTRX1, MLL

NCBI Gene: 4297ENSG00000118058UniProt: Q03164

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

Primary Disease Associations & Inheritance

Wiedemann-Steiner syndromeMIM #605130
AD
552
ClinVar variants
58
Pathogenic / LP
1.00
pLI score· haploinsufficient
12
Active trials
Clinical Summary— KMT2A
🧬
Gene-Disease Validity (ClinGen)
Wiedemann-Steiner syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 326 VUS of 552 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.07LOEUF
pLI 1.000
Z-score 11.38
OE 0.03 (0.01–0.07)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
6.23Z-score
OE missense 0.61 (0.59–0.64)
1271 obs / 2067.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.59–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 5 / 160.7Missense obs/exp: 1271 / 2067.9Syn Z: 2.24

ClinVar Variant Classifications

552 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic24
VUS326
Likely Benign165
Benign1
Conflicting2
34
Pathogenic
24
Likely Pathogenic
326
VUS
165
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
0
9
0
34
Likely Pathogenic
9
7
8
0
24
VUS
2
305
19
0
326
Likely Benign
0
12
41
112
165
Benign
0
0
0
1
1
Conflicting
—2
Total3632477113552

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

KMT2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KMT2A-related Wiedemann-Steiner syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Wiedemann-Steiner syndrome

MIM #605130

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KMT2A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).
Issa GC et al.·J Clin Oncol
2025Clinical trial
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.
Issa GC et al.·Nature
2023Clinical trial
The genomic landscape of pediatric acute lymphoblastic leukemia.
Brady SW et al.·Nat Genet
2022
Neonatal leukaemia.
Roberts I et al.·Br J Haematol
2018Review
The KMT2A recombinome of acute leukemias in 2023.
Meyer C et al.·Leukemia
2023
Infant Acute Lymphoblastic Leukemia-New Therapeutic Opportunities.
Kulczycka M et al.·Int J Mol Sci
2024Review
How I treat refractory and relapsed acute myeloid leukemia.
Thol F et al.·Blood
2024
Precision medicine in acute lymphoblastic leukemia.
Pui CH·Front Med
2020Review
Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.
Wang ES et al.·Lancet Oncol
2024Clinical trial
Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia.
Uckelmann HJ et al.·Cancer Discov
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Leukemia, Myeloid, Acute

A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)

RECRUITING
NCT06852222Phase PHASE3Janssen Research & Development, LLCStarted 2025-06-04
BleximenibVenetoclax (VEN)Azacitidine (AZA)
Acute Myeloid Leukemia

Clinical Study Protocol for the Treatment of ND-AML and RR-AML With KMT2A Gene Abnormalities Using VHEA.

RECRUITING
NCT06328179Phase NAHuai'an First People's HospitalStarted 2022-05-24
Venetoclax 100 mg d1，200 mg d2，400 mg d3-14；
ALL, AdultAML, AdultAcute Leukaemia

A Study of BN104 in the Treatment of Acute Leukemia

ACTIVE NOT RECRUITING
NCT06052813Phase PHASE1, PHASE2Institut de Recherches Internationales Servier (I.R.I.S.)Started 2023-10-19
BN104 monotherapyBN104 monotherapyBN104 monotherapy - rp2d
Acute Myeloid Leukemia With KMT2A RearrangementAcute Myeloid Leukemia With NPM1 Mutation

Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene

RECRUITING
NCT05886049Phase PHASE1National Cancer Institute (NCI)Started 2024-06-20
Biospecimen CollectionBone Marrow AspirationBone Marrow Biopsy
Leukemia, Myeloid, AcuteLeukemia, Lymphocytic, Acute

A Study of DSP-5336 in Relapsed/Refractory AML/ ALL With or Without MLL Rearrangement or NPM1 Mutation

RECRUITING
NCT04988555Phase PHASE1, PHASE2Sumitomo Pharma America, Inc.Started 2022-02-28
EnzomenibazolesVenetoclax
Acute Lymphoblastic Leukemia, PediatricALL, Infants

Combined Immuno-chemotherapy for Patients With B-linear Acute Lymphoblastic Leukemia Diagnosed From 0 to 365 Days of Life (ALL-Baby-2021)

RECRUITING
NCT05029531Phase PHASE3Federal Research Institute of Pediatric Hematology, Oncology and ImmunologyStarted 2021-09-23
the risk-adapted choice of therapy and the use of a combination of chemotherapy with immunotherapy and hematopoietic stem cell transplantation for patients with risk factors.
Acute Leukemia of Ambiguous LineageB Acute Lymphoblastic Leukemia

Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

RECRUITING
NCT06317662Phase PHASE2National Cancer Institute (NCI)Started 2025-06-05
Asparaginase Erwinia chrysanthemiBiospecimen CollectionBlinatumomab
Acute Myeloid Leukemia

Ziftomenib for the Treatment of Patients With NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia Not Eligible for Standard Therapy

NOT YET RECRUITING
NCT06930352Phase PHASE2Uma BorateStarted 2026-01-10
Biospecimen CollectionBone Marrow AspirationBone Marrow Biopsy
Acute Myeloid LeukemiaAcute Lymphoblastic LeukemiaMixed Lineage Acute Leukemia

A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

RECRUITING
NCT04065399Phase PHASE1, PHASE2Syndax PharmaceuticalsStarted 2019-11-05
revumenibcobicistat
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2AFibroblast Growth Factor Basic Form MeasurementFLT3 Internal Tandem Duplication

Nintedanib and Azacitidine in Treating Participants With HOX Gene Overexpression Relapsed or Refractory Acute Myeloid Leukemia

ACTIVE NOT RECRUITING
NCT03513484Phase PHASE1Northwestern UniversityStarted 2018-11-14
AzacitidineLaboratory Biomarker AnalysisNintedanib
Acute Myeloid Leukemia

Bleximenib in Combination With Standard Induction and Consolidation Therapy Followed by Maintenance for Treatment of Patients With Acute Myeloid Leukemia (AML)

NOT YET RECRUITING
NCT07223814Phase PHASE3Stichting Hemato-Oncologie voor Volwassenen NederlandStarted 2025-12
BleximenibCytarabineDaunorubicin or Idarubicin

External Resources

Links to major genomics databases and tools