DNMT3A

Chr 2AD

DNA methyltransferase 3 alpha

Also known as: DNMT3A2, HESJAS, M.HsaIIIA, TBRS

NCBI Gene: 1788 ENSG00000119772 UniProt: Q9Y6K1 OMIM: 602769

The protein functions as a de novo DNA methyltransferase that establishes genome-wide DNA methylation patterns essential for normal development, genomic imprinting, and transcriptional regulation. Germline mutations cause Tatton-Brown-Rahman syndrome and Heyn-Sproul-Jackson syndrome, both presenting with intellectual disability, overgrowth, and distinctive facial features, while somatic mutations are associated with acute myeloid leukemia. Inheritance is autosomal dominant, and the gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 1.583 OMIM phenotypes

Clinical Summary— DNMT3A

🧬

Gene-Disease Validity (ClinGen)

Heyn-Sproul-Jackson syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

1.58LOEUF

pLI 0.000

Z-score -1.52

OE 1.26 (1.00–1.58)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

3.45Z-score

OE missense 0.59 (0.54–0.65)

339 obs / 570.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE1.26 (1.00–1.58)

0≤0.351.4

Missense OE0.59 (0.54–0.65)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 52 / 41.4Missense obs/exp: 339 / 570.7Syn Z: 0.63

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDNMT3A-related microcephalic primordial dwarfismGOFAD

definitiveDNMT3A-related Tatton-Brown Rahman syndrome (overgrowth syndrome with intellectual disability)LOFAD

0.3892th %ile

GOF

0.4480th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-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.

LOF1 literature citation

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe most frequent DNMT3A mutation in AML patients (R882H) encodes a dominant-negative protein that reduces methyltransferase activity by ?80% in cells with heterozygous mutations, causing a focal, canonical DNA hypomethylation phenotype; this phenotype is partially recapitulated in murine Dnmt3a -/-PMID:31996479

GOFThe three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient's ETP-ALL from clonal hematopoiesis.PMID:27148573

LOFDNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.PMID:27016502

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

DNMT3A · 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

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

Bone Marrow Failure DisordersVEXAS SyndromeHemoglobinurea, Paroxysmal

Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study

ENROLLING BY INVITATION

NCT07102849National Heart, Lung, and Blood Institute (NHLBI)Started 2025-09-09

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

Lung Cancer

Feasibility of Targeted Bronchial Washing for Molecular Testing by Next Generation Sequencing in Early-stage Lung Cancer

ACTIVE NOT RECRUITING

NCT06301295Phase NAPusan National University HospitalStarted 2024-05-29

Ultarthin bronchoscopy with intratumoral washing

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

Myeloproliferative Neoplasm

Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

RECRUITING

NCT06022328University Hospital, BordeauxStarted 2023-12-15

Assessment of the epigenetic age

Peripheral T-Cell Lymphoma

Real-world Outcomes of Peripheral T-cell Lymphoma: A Multicenter Retrospective and Prospective Cohort Study

RECRUITING

NCT07270861Fudan UniversityStarted 2025-11-15

Observational

Leukemia, Myeloid, AcuteMyeloid DysplasiaOvarian Epithelial Cancer

Genetic Landscape in Women with Metastatic Ovarian Cancer Before and During Treatment with PARP Inhibitors

RECRUITING

NCT06785077Phase NAEuropean Institute of OncologyStarted 2020-10-02