 Abstract multiple SARS-CoV-2 omega subvariants have been identified, including BA.2, BA.2.12.1, BA.4, and BA.5. BA.5 has become the dominant strain globally. Additionally, BA.2.75 is increasing in certain countries. To explore their receptor binding and interspecies transmission risks, we examined the binding capacities of human and other 28 animal ACE2 orthologs towards S proteins of these subvariants. The binding affinity between HACE2 and these subvariants remained within the range of previous VOI and VOC coronavirus strains. Notably, our 493-Q reverse mutation enhanced the binding of ACE2S from humans and many animals closely related to humans, suggesting an increased risk of cross-species transmission. Structure determination of S-HACE2 or RBD-HACE2 complexes for these subvariants and BA.2S binding to ACE2 of mouse, rat, or golden hams to reveal the molecular basis for receptor binding and broader interspecies recognition. This article was authored by Shenan Zhao, Yufeng Xie, Bin Bai, and others. We are article.tv, links in the description below.