KMT2D

Chr 12

lysine methyltransferase 2D

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

NCBI Gene: 8085 ENSG00000167548 UniProt: O14686

This gene encodes a histone methyltransferase that catalyzes H3K4 methylation as part of chromatin remodeling machinery, functioning in transcriptional activation and DNA repair. Mutations cause Kabuki syndrome 1, a multisystem disorder characterized by distinctive facial features, intellectual disability, growth deficiency, and variable anomalies including cardiac defects, hearing loss, and endocrine abnormalities. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— KMT2D

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Gene-Disease Validity (ClinGen)

Kabuki syndrome 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.04–0.10)

0≤0.351.4

Missense OE?0.81 (0.79–0.84)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 15 / 224.4Missense obs/exp: 2541 / 3127.8Syn Z: -1.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKMT2D-related multiple malformations syndrome (BCAHH)OTHERAD

definitiveKMT2D-related Kabuki syndromeLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.09100th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNUnlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.1

LOFHaploinsufficiency of KMT2D is sufficient to cause Kabuki syndrome and is compatible with life.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Rare Fetal Genetic DiseasesCongenital Malformation

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

RECRUITING

NCT06475651Assistance Publique - Hôpitaux de ParisStarted 2026-02-26

Methylation analysis

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

Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING

NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19

Usual Care GroupControlled exercise with telerehabilitation

PTCLRefractory

Genotype-guided Targeted Agents Plus EZH2i for Primary Refractory PTCL

NOT YET RECRUITING

NCT07493330Phase PHASE1, PHASE2Ruijin HospitalStarted 2026-03-23

Zeprumetostat+AzacitadineZeprumetostat+DecitabineZeprumetostat+Chidamide

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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

KMT2D promotes proliferation of gastric cancer cells: evidence from ctDNA sequencing

Li Q et al.·J Clin Lab Anal

2021