The crystal structure of the DNMT3B‐3L‐DNA complex has served as a foundation for elucidating the potential enzymatic or complex assembly defects of most ICF syndrome‐linked mutations, such as those affecting cofactor S‐adenosylmethionine binding (A585V, A603T, and V606A), stabilization of protein folding (A603T, V726G, A766P, R840Q), and DNA binding (R823G). Here, DNMT3B is linked to ICF syndrome.