DNMT3A, as de novo DNA methyltransferase, is essential for regulating gene expression through cellular development and differentiation. The functions of DNMT3A rely on its oligomeric states and allosteric regulations between its catalytic domain and binding partners. The DNMT3A R882H mutation is frequently observed in acute myeloid leukemia (AML). It is located in the subunit and DNA binding interface of DNMT3A and has been reported to cause a reduction in activity and dominant negative effects. DNMT3A regulation of miR-2b controls cardiac fibroblast autophagy during cardiac fibrosis and provide a basis for the development of therapies for cardiac fibrosis. DNMT3A variants are present in elderly healthy individuals and patients with AML in complete remission, which suggests that DNMT3A mutations may contribute to pre-leukemic clonal hematopoiesis.