KMT2A
Chr 11ADlysine methyltransferase 2A
Also known as: ALL-1, ALL1, CXXC7, GAS7, HRX, HTRX, HTRX1, MLL
This protein functions as a histone H3 lysine 4 methyltransferase that regulates gene expression during early development by mediating chromatin modifications associated with transcriptional activation, including regulation of HOX genes. Mutations cause Wiedemann-Steiner syndrome through an autosomal dominant inheritance pattern, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, supporting haploinsufficiency as the primary disease mechanism.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
400 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 22 | 0 | 1 | 0 | 23 |
Likely Pathogenic | 0 | 4 | 0 | 0 | 4 |
VUS | 4 | 177 | 13 | 0 | 194 |
Likely Benign | 0 | 4 | 34 | 116 | 154 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 3 | |||
| Total | 26 | 185 | 48 | 116 | 378 |
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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Nintedanib and Azacitidine in Treating Participants With HOX Gene Overexpression Relapsed or Refractory Acute Myeloid Leukemia
ACTIVE NOT RECRUITINGA Study of BN104 in the Treatment of Acute Leukemia
ACTIVE NOT RECRUITINGA Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)
RECRUITINGA Real-world Study on the Efficacy and Safety of Menin Inhibitors as Maintenance After Allo-HSCT
RECRUITINGSNDX-5613 and Gilteritinib for the Treatment of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia and Concurrent MLL-Rearrangement or NPM1 Mutation
RECRUITINGClinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML
RECRUITINGOnline Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
RECRUITINGA Study of SNDX-5613 in Combination With Intensive Chemotherapy in Participants With Acute Myeloid Leukemias
RECRUITINGRevumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML
RECRUITINGCombined Immuno-chemotherapy for Patients With B-linear Acute Lymphoblastic Leukemia Diagnosed From 0 to 365 Days of Life (ALL-Baby-2021)
RECRUITINGA Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation
RECRUITINGZiftomenib for the Treatment of Patients With NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia Not Eligible for Standard Therapy
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools