KMT2D

Chr 12AD

lysine methyltransferase 2D

Also known as: AAD10, ALR, BCAHH, CAGL114, KABUK1, KMS, MLL2, MLL4

NCBI Gene: 8085ENSG00000167548UniProt: O14686

The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

Primary Disease Associations & Inheritance

Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndromeMIM #620186
AD
Kabuki syndrome 1MIM #147920
AD
7432
ClinVar variants
3
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— KMT2D
⚡
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
3 Pathogenic / Likely Pathogenic· 116 VUS of 7432 total submissions
💊
Clinical Trials
4 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.
0.10LOEUF
pLI 1.000
Z-score 12.95
OE 0.07 (0.04–0.10)
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.
3.73Z-score
OE missense 0.81 (0.79–0.84)
2541 obs / 3127.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.07 (0.04–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.79–0.84)
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.1.05
0≤1.21.6
LoF obs/exp: 15 / 224.4Missense obs/exp: 2541 / 3127.8Syn Z: -1.43

ClinVar Variant Classifications

7432 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic2
VUS116
Likely Benign54
Benign27
1
Pathogenic
2
Likely Pathogenic
116
VUS
54
Likely Benign
27
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
2
0
0
0
2
VUS
0
112
2
2
116
Likely Benign
0
11
16
27
54
Benign
0
19
0
8
27
Total21421937200

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

View in ClinVar →

Protein Context — Lollipop Plot

KMT2D · protein map & ClinVar variants

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

Gene2Phenotype Curations

KMT2D-related multiple malformations syndrome (BCAHH)

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

KMT2D-related Kabuki syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

MIM #620186

Molecular basis of disorder known

Autosomal dominant

Kabuki syndrome 1

MIM #147920

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Kabuki Syndrome-Clinical Review with Molecular Aspects.
Boniel S et al.·Genes (Basel)
2021Review
KMT2C and KMT2D aberrations in breast cancer.
Tinsley E et al.·Trends Cancer
2024Review
High-risk MCL: recognition and treatment.
Jain P et al.·Blood
2025Review
Mantle cell lymphoma in 2022-A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments.
Jain P et al.·Am J Hematol
2022
Kabuki syndrome: international consensus diagnostic criteria.
Adam MP et al.·J Med Genet
2019
Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.
Rots D et al.·Am J Hum Genet
2024
Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma.
Shen R et al.·Signal Transduct Target Ther
2023
Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.
Nann D et al.·Blood Adv
2020
Identification of genomic alterations in oesophageal squamous cell cancer.
Song Y et al.·Nature
2014
Parathyroid Carcinoma.
Cetani F et al.·Front Horm Res
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
The Histone Methyltransferase KMT2D Is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration-Resistant Prostate Cancer.
Kittane S et al.·Cancer Res
2026
YTH Domain Family 2 Promotes Tubal Factor Infertility through Reducing H3K4me1 Methylation of CYLD by KMT2D.
Shao L et al.·Appl Biochem Biotechnol
2026
KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.
Chen N et al.·Cell Death Differ
2026
Role of histone-lysine N-methyltransferase 2D (KMT2D) in MEK-ERK signaling-mediated epigenetic regulation: a phosphoproteomics perspective.
Kammarambath SR et al.·Front Bioinform
2025🔓 Open Access
Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression.
Wen H et al.·Mol Biomed
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Giant Cell ArteritisTemporal ArteritisClonal Hematopoiesis of Indeterminate Potential

Clonal Hematopoiesis in Giant Cell Arteritis

NOT YET RECRUITING
NCT06244069ASST Fatebenefratelli SaccoStarted 2024-03
Temporal arterial biopsyWhole exome sequencingSingle cell transcriptomics
Metastatic Bladder Urothelial CarcinomaMetastatic Malignant Solid NeoplasmStage IV Bladder Cancer AJCC v8

Pemetrexed Response in Relation to Tumor Alterations of Gene Status for the Treatment of Patients With Metastatic Urothelial Bladder Cancer and Other Solid Tumors

RECRUITING
NCT06630416Phase PHASE2Northwestern UniversityStarted 2024-11-27
Biospecimen CollectionComputed TomographyPemetrexed
Rare Fetal Genetic DiseasesCongenital Malformation

Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset

NOT YET RECRUITING
NCT06475651Assistance Publique - Hôpitaux de ParisStarted 2024-06
Methylation analysis
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools