Genetic mutations have long been identified as contributors to ALS, however, their molecular-consequences have remained elusive. To address this, we analysed the effects of ALS missense mutations in SOD1, FUS and TDP-43 using in silico tools. FUS and TDP-43 mutations affected disordered regions associated with phase separation and aggregation, while SOD1 mutations destabilized the homodimer, which is linked to toxic trimer formation. Furthermore, we compiled 1,343 clinical missense mutations spanning 111 genes, into the most comprehensive resource of mutations clinically associated with ALS. This database, along with our analysis pipeline, offers clinicians an insightful resource to aid efficient ALS diagnosis. (By Dr. David Ascher, https://jmg.bmj.com/content/early/2022/09/30/jmg-2022-108798)