In recent years, germline mutations that cause structural destabilization and subsequent protein misfolding have surfaced as the cause of several diseases, including cystic fibrosis (Ahner et al., 2007), phenylketonuria (Pey et al., 2007; Scheller et al., 2019), early onset Parkinson’s disease (Mathiassen et al., 2015; Olzmann et al., 2004) and MSH2-linked LS (Arlow et al., 2013; Nielsen et al., 2017). The gene discussed is MSH2; the disease is cystic fibrosis.