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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains a formidable challenge to worldwide public health. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. We comprehensively investigated the impact of RBD mutations, including 6 variants of concern (VOC) or interest (Alpha, Beta, Gamma, Delta, Kappa and Omicron) and 33 common point mutations, on IgG recognition, FcγR-engagement, and ACE2-binding inhibition in plasma from BNT162b2-vaccine recipients (two-weeks following second dose) and mild-to-moderate COVID-19 convalescent subjects using our custom bead-based 39-plex array. We observed that IgG-recognition and FcγR-binding antibodies were most profoundly decreased against Beta and Omicron RBDs, as well as point mutations G446S, found in Omicron, and N501T, a key mutation found in animal adapted SARS-CoV-2 viruses. Measurement of RBD-ACE2 binding affinity via Biolayer Interferometry showed all VOC RBDs have enhanced affinity to human ACE2. Furthermore we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695), K26R (rs4646116) and S19P (rs73635825), have altered binding kinetics to the RBD of VOCs potentially affecting virus-host interaction and thereby host susceptibility.