Here, we aimed to provide a comprehensive overview of the significance of the spike mutations of the Delta, BA.1, and BA.2 variants, focusing on ACE-2 affinity, protein stability, and glycosylation; and their contribution to evasion of recognition by vaccine- and infection-induced antibodies, T cells, and the humoral innate immune pattern recognition molecule mannose-binding lectin (MBL). The gene discussed is ACE2; the disease is infection.