The deleterious consequences of genetic and posttranslational abnormalities of TMEM43 underscore indispensable missions of its structure-function relationships in the pathogenesis of a spectrum of human health and disease states affecting multiple organ systems and ranging from severe ARVC5 to muscular dystrophies, hearing loss, and various cancers. Here, TMEM43 is linked to arrhythmogenic right ventricular dysplasia 5.