PSORS1C2 is a mammalian-specific gene located within the psoriasis susceptibility locus 1 (PSORS1) on chromosome 6 that encodes a keratinocyte cornification-associated protein involved in terminal epidermal differentiation. Phylogenetic analysis reveals PSORS1C2 originated in evolutionarily basal mammals and has undergone gene inactivation in aquatic mammals lacking skin barrier function, suggesting critical roles in skin development 1. In human tissues, PSORS1C2 expression is primarily epidermal, with strong upregulation during keratinocyte terminal differentiation in vitro and exclusive immunohistochemical localization to the granular epidermal layer and thymic Hassall's corpuscles 1. PSORS1C2 dysfunction is implicated in multiple skin barrier diseases. Reduced PSORS1C2 expression correlates with terminal differentiation defects in atopic dermatitis (AD), particularly detectable through non-invasive tape-stripping 2, and decreased expression is observed in pediatric AD patients 3. Notably, homozygous deletion of PSORS1C2 and neighboring genes causes peeling skin disease, though CDSN deletion was the primary contributor 4. Additionally, depleted protein-altering variants in PSORS1C2 were identified in leprosy cases, implicating it as a candidate susceptibility gene 5. Recent genome-wide association studies identified PSORS1C2 variants (rs1265159) showing sex-differential effects on HIV viral load 6 and associations with depression when analyzed across psychiatric disorders 7. These findings position PSORS1C2 as a multifunctional epidermal barrier protein with broader genetic associations in complex diseases.