Rapp–Hodgkin syndrome (RHS) is an autosomal dominant disorder characterized by ectodermal dysplasia and cleft lip/cleft palate. Very recently, mutations in p63 have been identified as a cause of RHS; to date five such mutations have been identified. We describe a Thai girl with RHS. She had short stature, ectodermal dysplasia, epiphora, cleft lip, cleft palate, and normal development. Mutation analysis for the entire coding region of p63 identified a novel and de novo mutation, 1622C[RIGHTWARDS ARROW]A (S541Y), in the SAM domain, predicting an abnormal α tail of the p63α protein isotypes. This observation supports that majority of patients with RHS are caused by mutations affecting the tail of p63α, a region that also contains most of the pathogenic mutations in ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome.