RUFY2 is a RUN and FYVE domain-containing protein localized to the cytoplasm and endosomes that functions in endocytic regulation. The RUN domain of RUFY2 specifically binds to Rab33, a small GTPase involved in Rab-mediated membrane trafficking 1. RUFY2 contains regulatory domains including a RUN domain and coiled-coil domain that can be fused to the RET tyrosine kinase in oncogenic rearrangements 23. In cancer biology, RUFY2-RET fusions have been identified in both lung cancer and papillary thyroid carcinoma, where the fusion protein juxtaposes RET's kinase domain with RUFY2's regulatory domains, potentially driving tumorigenesis 23. RUFY2 is frequently mutated at coding mononucleotide repeats in microsatellite-instable cancers, occurring in 50% of MSI-H cell lines 4. Beyond cancer, RUFY2 has emerged as a novel migraine susceptibility gene through transcriptome-wide association analysis, with genetically predicted expression associated with migraine risk 5. Additionally, RUFY2 appears dysregulated in glioblastoma through competitive endogenous RNA networks involving miRNA regulation 6, and shows dosage-sensitive regulation by miR-155 and miR-802 in Down syndrome models 7. These findings suggest RUFY2 plays roles in both membrane trafficking and disease pathophysiology across multiple contexts.