SARS-CoV-2 variants have evolved critical mutations causing antigenicity changes and immune escape. This study profiles Omicron and other variants using computational interface analysis and in vitro assays. Critical mutations impacting 14 antibodies' neutralization efficiency were identified, revealing diverse molecular mechanisms. Omicron showed exceptional immune escape potency. The study highlights computational interface analysis for SARS-CoV-2 mutation surveillance and early identification of concerning variants, guiding neutralizing antibody therapy.