The genetic code is degenerate. Eighteen of the twenty core amino acids are each encoded by multiple, so-called synonymous codons. The Neutral Theory of Molecular Evolution suggests that synonymous codons will be unaffected by the selective evolutionary pressure and that synonymous mutations will be inconsequential to protein quality. However, recent reports refute this prediction. A new study uncovers the mechanism(s) underlying the origin of Hemophilia B in patients harboring a single synonymous mutation in the F9 gene encoding blood coagulation factor IX. The key novel finding from this study is that a single synonymous mutation results in clinical consequences that lead to a disease via multiple mechanisms that act in concert. (By Vijaya L Simhadri, http://jmg.bmj.com/content/early/2016/12/22/jmedgenet-2016-104072 )