LRCH3 (leucine rich repeats and calponin homology domain containing 3) is a cytosolic protein involved in regulating the actin cytoskeleton through septin organization. As part of the DISP complex, LRCH3 may regulate the association of septins with actin filaments, thereby influencing septin ring and cytoskeleton organization. Clinically, LRCH3 has been identified as a fusion partner in melanoma pathogenesis. LRCH3::RAF1 fusions were detected in 2 of 40 melanomas (0.6% of a 7119-melanoma cohort) characterized by activating RAF1 structural variants 1. These LRCH3::RAF1 fusion-positive melanomas were triple wild-type for BRAF, NRAS, and NF1, representing 2.1% of triple wild-type melanomas overall, and frequently harbored additional mutations in TERTp (62%) and CDKN2A (60%) 1. In a separate clinical cohort, LRCH3::RAF1 was identified as one of 16 gene fusions detected across 750 melanomas, with potential therapeutic implications 2. Additionally, LRCH3 was identified as a candidate susceptibility gene associated with humoral immune response to Mycobacterium avium subspecies paratuberculosis in dairy cattle, suggesting a potential role in immune regulation 3. These findings indicate LRCH3 functions in cytoskeletal regulation and may contribute to melanoma oncogenesis when dysregulated through kinase fusion events.