PRPH2 is a glycosylated tetraspanin protein that plays a crucial role in outer segment morphogenesis. The protein induces membrane curvature at the rim and orchestrates proper disc elaboration by forming a complex network of homo- and hetero-oligomers, primarily mediated through its EC2/D2 loop. This loop, a functionally and structurally essential domain shared by all tetraspanins, is divided into two subdomains responsible for diverse interactions. Pathological mutations in the EC2/D2 loop account for nearly 70% of all PRPH2 mutations, resulting in a spectrum of heterogenous disease phenotypes. In this chapter, we provide an overview of the structural elements of the EC2/D2 loop of PRPH2 and explore the cellular and biochemical consequences of known mutations.