Cover: The giant muscle protein obscurin is expressed in several isoforms, all of which are composed of immunoglobulin (Ig), fibronectin-like (Fn3) domains and signalling domains: a GEF-domain in large isoform A and B, and two protein kinase domains in isoform B. Missense variants in Ig58 and Ig59 have been implicated in cardiomyopathy. Fukuzawa et al. used biophysical and biochemical analyses to demonstrate that these variants do not impact on stability or protein-protein interactions. In agreement with the common occurrence of these variants, this highlights that careful assessment of variant frequency and experimental biophysical impact need to considered before declaring a variant as pathogenic.