DNMT3A is a de novo DNA methyltransferase essential for establishing genome-wide DNA methylation patterns during development and gametogenesis 1. It functions in a non-processive manner, methylating both CpG and non-CpG sites, and coordinates with histone methylation to regulate chr2 structure 1. DNMT3A plays critical roles in genomic imprinting and acts as a transcriptional corepressor by recruiting histone deacetylase activity 1. Clinically, DNMT3A mutations are highly relevant to hematologic malignancies. Frequent DNMT3A mutations in acute myeloid leukemia (AML) represent early leukemogenic events associated with poor prognosis 2. The hotspot R882H mutation promotes AML development through NAM-NAD metabolic reprogramming, accelerating cell cycle progression 3. Beyond AML, somatic DNMT3A mutations drive clonal hematopoiesis, conferring increased cardiovascular disease risk; patients with DNMT3A mutations and ST-segment elevation myocardial infarction show elevated inflammatory cytokines and worse outcomes 45. Germline DNMT3A variants cause Tatton-Brown-Rahman syndrome, characterized by overgrowth, intellectual disability, and emerging cardiovascular complications including aortic dilatation and cardiomyopathy 6. Additionally, DNMT3A regulates osteoclastogenesis through FoxO3 promoter methylation, with therapeutic implications for osteoporosis treatment 7.