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.

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…

MultiplemechanismADLOEUF 1.583 OMIM phenotypes

Clinical Summary— DNMT3A

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Gene-Disease Validity (ClinGen)

Heyn-Sproul-Jackson syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

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

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ClinVar Variants

215 unique Pathogenic / Likely Pathogenic· 483 VUS of 1312 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDNMT3A-related microcephalic primordial dwarfismGOFAD

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

This gene — mechanism propensity

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 · 64% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

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 -/-1

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.2

LOFDNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.3

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

1312 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic122

Likely Pathogenic93

VUS483

Likely Benign509

Benign27

Conflicting33

122

Pathogenic

Likely Pathogenic

483

VUS

509

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	95	21	6	0	122
Likely Pathogenic	43	46	3	1	93
VUS	15	433	25	10	483
Likely Benign	1	13	126	369	509
Benign	0	1	23	3	27
Conflicting	—				33
Total	154	514	183	383	1,267

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap DNMT3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

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

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GeneReview available — DNMT3A

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

DNMT3A Gene Mutation

Metformin Inhibits DNMT3A Clonal Hematopoiesis in Acute Leukemia

NOT YET RECRUITING

NCT07188740Phase PHASE1Institute of Hematology & Blood Diseases Hospital, ChinaStarted 2025-10-30

Metformin

ST-elevation Myocardial Infarction (STEMI)Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Clonal Hematopoiesis of Indeterminate Potential and Infarct Severity in ST-Elevation Myocardial Infarction

NOT YET RECRUITING

NCT07615023Medical University InnsbruckStarted 2026-06-20

Clonal hematopoiesis assessment and cardiac magnetic resonance imaging

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

buccal cellsbone marrow cellsperipheral blood cells

Diffuse Large B Cell Lymphoma

Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

RECRUITING

NCT06161896Lars Møller PedersenStarted 2024-05-06

Stool samples

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

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

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

Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING

NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16