DNMT3A

Chr 2AD

DNA methyltransferase 3 alpha

Also known as: DNMT3A-3, 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Acute myeloid leukemia, somaticMIM #601626

Heyn-Sproul-Jackson syndromeMIM #618724

Tatton-Brown-Rahman syndromeMIM #615879

UniProtLeukemia, acute myelogenous

Clinical highlights

Gene-disease validity (ClinGen)

Heyn-Sproul-Jackson syndrome · ADLimitednot for standalone diagnostic reporting2 gene-disease associations curated in total

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

844

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.58

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — DNMT3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?1.26 (1.00–1.58)

0≤0.351.4

Missense OE?0.59 (0.54–0.65)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

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

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.

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

📖

GeneReview available — DNMT3A

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Polycythemia Vera

Pegylated Interferon α-2b in Combination With Ruxolitinib for Treating Hydroxyurea-resistant/Intolerant PV

RECRUITING

NCT05870475Phase PHASE2Institute of Hematology & Blood Diseases Hospital, ChinaStarted 2023-06-30

RuxolitinibPegylated interferon α-2b

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

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

Myelodysplastic SyndromeAcute Myeloid Leukemia

Evaluating Myelodysplastic Syndrome Risks in NET Patients Planned for Peptide Radionuclide Therapy

RECRUITING

NCT06510868University Health Network, TorontoStarted 2024-08-01

Peptide receptor radionuclide therapy (PRRT)Blood collection