ALS2CL (ALS2 C-terminal like) is a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 that modulates endosome dynamics 1. The protein shares homology with the C-terminal region of ALS2, the causative gene for juvenile amyotrophic lateral sclerosis 1. ALS2CL exhibits specific but relatively weak Rab5-GEF activity paired with strong Rab5-binding properties, inducing characteristic tubulation of endosome compartments when co-expressed with Rab5A in cells 1. Functionally, ALS2CL exists primarily as a homodimer that interacts with ALS2 oligomers to form large heteromeric complexes, dominant-suppressing ALS2-induced endosome enlargement and generating perinuclear tubulo-membranous structures dependent on ALS2CL-ALS2 interaction 2. The protein contains the VPS9 domain characteristic of Rab5 GEFs 3. Clinically, ALS2CL has emerged as a diagnostic candidate gene for osteoporosis with concomitant sarcopenia 4 and a component of alternative splicing-based prognostic signatures for prostate cancer biochemical recurrence 5. ALS2CL is widely expressed in lacrimal functional unit tissues and other tissues 6, indicating broader physiological roles beyond motor neuron function.