Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and a median survival of 3-5 years post-diagnosis. While the etiology of ALS remains elusive, mutations in SOD1, encoding the Cu/Zn superoxide dismutase enzyme, are strongly associated with familial ALS (fALS). These mutations promote a toxic gain-of-function, primarily through SOD1 misfolding and aggregation. We systematically assessed 244 SOD1 missense mutations using a multi-tiered computational framework encompassing structural, functional, and pathogenic predictors. Sequence-based predictors (SIFT, PolyPhen-2, FATHMM) and structure-guided tools (mCSM, PremPS, DynaMut2) identified 79 destabilizing mutations, 64 of which were classified as pathogenic by phenotype predictors (PhD-SNP, SNPs&GO, MutPred2). Twelve mutations resided in evolutionarily conserved regions, with eight (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I) exhibiting pronounced aggregation propensity via SODA analysis. Notably, H72Y disrupts a zinc-binding residue critical for structural integrity and catalysis. Protein-protein interaction networks linked SOD1 to ALS-associated pathways, highlighting its involvement in oxidative stress and protein homeostasis. Our integrative approach highlights the power of computational genomics in unraveling mutation-driven SOD1 dysfunction, offering mechanistic insights into ALS pathogenesis and guiding therapeutic strategies focused on aggregation-prone variants.