DNMT3A

Chr 2AD

DNA methyltransferase 3 alpha

NCBI Gene: 1788ENSG00000119772UniProt: Q9Y6K1

Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development (PubMed:12138111, PubMed:16357870, PubMed:30478443). DNA methylation is coordinated with methylation of histones (PubMed:12138111, PubMed:16357870, PubMed:30478443). It modifies DNA in a non-processive manner and also methylates non-CpG sites (PubMed:12138111, PubMed:16357870, PubMed:30478443). May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1 (By similarity). Plays a role in paternal and maternal imprinting (By similarity). Required for methylation of most imprinted loci in germ cells (By similarity). Acts as a transcriptional corepressor for ZBTB18 (By similarity). Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites (By similarity). Can actively repress transcription through the recruitment of HDAC activity (By similarity). Also has weak auto-methylation activity on Cys-710 in absence of DNA (By similarity)

Primary Disease Associations & Inheritance

Acute myeloid leukemia, somaticMIM #601626
Heyn-Sproul-Jackson syndromeMIM #618724
AD
Tatton-Brown-Rahman syndromeMIM #615879
AD
UniProtLeukemia, acute myelogenous
563
ClinVar variants
78
Pathogenic / LP
0.00
pLI score
12
Active trials
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.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 243 VUS of 563 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
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?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.
3.45Z-score
OE missense 0.59 (0.54–0.65)
339 obs / 570.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?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.1.26 (1.00–1.58)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.54–0.65)
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.0.95
0≤1.21.6
LoF obs/exp: 52 / 41.4Missense obs/exp: 339 / 570.7Syn Z: 0.63

ClinVar Variant Classifications

563 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic33
VUS243
Likely Benign239
Benign1
Conflicting2
45
Pathogenic
33
Likely Pathogenic
243
VUS
239
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
4
16
0
45
Likely Pathogenic
14
14
5
0
33
VUS
3
221
15
4
243
Likely Benign
0
3
54
182
239
Benign
0
1
0
0
1
Conflicting
—2
Total4224390186563

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

View in 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.

Gene2Phenotype Curations

DNMT3A-related microcephalic primordial dwarfism

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

DNMT3A-related Tatton-Brown Rahman syndrome (overgrowth syndrome with intellectual disability)

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

Acute myeloid leukemia, somatic

MIM #601626

Molecular basis of disorder known

Heyn-Sproul-Jackson syndrome

MIM #618724

Molecular basis of disorder known

Autosomal dominant

Tatton-Brown-Rahman syndrome

MIM #615879

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — DNMT3A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DNMT3A in Leukemia.
Brunetti L et al.·Cold Spring Harb Perspect Med
2017Review
Common and rare variant associations with clonal haematopoiesis phenotypes.
Kessler MD et al.·Nature
2022
Spectrum of clonal hematopoiesis in VEXAS syndrome.
Gutierrez-Rodrigues F et al.·Blood
2023
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
Yoshizato T et al.·N Engl J Med
2015
Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.
Sirenko M et al.·Blood
2024
The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.
Weinberg DN et al.·Nature
2019
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.
Prinzing B et al.·Sci Transl Med
2021
Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML.
Yang F et al.·Blood
2022Clinical trial
Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease.
Gumuser ED et al.·J Am Coll Cardiol
2023Cohort
Clonal Hematopoiesis and Risk of New-Onset Myocarditis and Pericarditis.
Schuermans A et al.·JAMA Cardiol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
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
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
Diffuse Large B Cell Lymphoma

Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

RECRUITING
NCT06161896Lars Møller PedersenStarted 2024-05-06
Stool samples
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
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

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

Ovary Syndrome for Efficient Diagnosis and Targeted Therapy

NOT YET RECRUITING
NCT06102629Phase NAAsian Institute of Gastroenterology, IndiaStarted 2023-11-05
laparoscopy / laparotomyNO INTERVENTION
CarcinomaNon-Small-Cell Lung CancerAdenocarcinoma

Synergistic Effect of Elemene Plus TKIs Compared With TKIs in EGFR-mutated Advanced NSCLC：Prospective Study

RECRUITING
NCT04401059Phase PHASE4Tian XieStarted 2020-11-09
Elemene plus first or third generation EGFR-TKIsFirst or third generation EGFR-TKIs
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
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
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

External Resources

Links to major genomics databases and tools