ARL6 is a small GTPase that functions as a key regulator of ciliary protein trafficking through its role in BBSome complex recruitment. In its GTP-bound state, ARL6 binds the BBS1 subunit of the BBSome coat complex at blades 1 and 7, enabling membrane targeting and subsequent trafficking of ciliary cargo proteins 1. This mechanism is critical for proper localization of membrane proteins including smoothened and GPCRs to primary cilia 2. ARL6 contributes to hedgehog pathway regulation by controlling SMO ciliary trafficking and participates in Wnt signaling and ciliary assembly/disassembly. ARL6 mutations cause Bardet-Biedl syndrome (BBS), an autosomal recessive ciliopathy characterized by pleiotropic effects including rod-cone dystrophy, renal anomalies, and polydactyly 3. Notably, one BBS patient with ARL6 mutations exhibited rod-sparing cone dystrophy, revealing phenotypic heterogeneity 4. ARL6 mutations are also associated with retinitis pigmentosa 55, with novel variants identified in retinal dystrophy cohorts 5. Recent evidence suggests ARL6 involvement in obesity-related pathways and adipocyte function, implicating it as a potential biomarker in obstructive sleep apnea 6. The protein's regulation by guanine nucleotide exchange factors and GTPase-activating proteins remains incompletely characterized 7.