C9orf72 is a component of the C9orf72-SMCR8 complex that regulates small GTPases, lysosomal integrity, and autophagy 1. The protein functions in multiple cellular processes including autophagy, endocytosis, and GTPase regulation through guanyl-nucleotide exchange factor activity [GO Annotations]. Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) 2. Disease pathogenesis involves three mechanisms: loss of C9orf72 protein function, toxic gain of function from repeat RNA, and dipeptide repeat proteins from repeat-associated translation 3. C9orf72 haploinsufficiency reduces protein levels and contributes to disease, with SMCR8 stabilizing C9orf72 through protection from proteasomal degradation mediated by the UBR5 E3 ligase 1. Pathological mechanisms include impaired nuclear speckle integrity causing global RNA splicing defects 4, DNA damage, altered phase separation, and nucleocytoplasmic transport defects 5. C9orf72 expansion carriers show shorter survival and more heterogeneous symptoms than non-expansion ALS patients 5. Emerging gene-silencing therapies for C9orf72 ALS underscore the need for improved diagnostic testing access 6.