DNMT3B and ICF syndrome: To gain deeper insights into the R823G mutation, we determined the first crystal structure of an ICF syndrome‐linked mutant of DNMT3B, that is the MTase domain of the DNMT3B‐3L hetero‐tetramer containing the R823G mutation at a resolution of 3.0 Å, demonstrating the underlying mechanism for its defects in DNA binding and methylation.