AbstractThe recent pandemic of COVID‐19, caused by SARS‐CoV‐2, is unarguably the most fearsome compared with the earlier outbreaks caused by other coronaviruses, SARS‐CoV and MERS‐CoV. Human ACE2 is now established as a receptor for the SARS‐CoV‐2 spike protein. Where variations in the viral spike protein, in turn, lead to the cross‐species transmission of the virus, genetic variations in the host receptor ACE2 may also contribute to the susceptibility and/or resistance against the viral infection. This study aims to explore the binding of the proteins encoded by different human ACE2 allelic variants with SARS‐CoV‐2 spike protein. Briefly, coding variants of ACE2 corresponding to the reported binding sites for its attachment with coronavirus spike protein were selected and molecular models of these variants were constructed by homology modeling. The models were then superimposed over the native ACE2 and ACE2‐spike protein complex, to observe structural changes in the ACE2 variants and their intermolecular interactions with SARS‐CoV‐2 spike protein, respectively. Despite strong overall structural similarities, the spatial orientation of the key interacting residues varies in the ACE2 variants compared with the wild‐type molecule. Most ACE2 variants showed a similar binding affinity for SARS‐CoV‐2 spike protein as observed in the complex structure of wild‐type ACE2 and SARS‐CoV‐2 spike protein. However, ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein. In summary, our data provide a structural basis of potential resistance against SARS‐CoV‐2 infection driven by ACE2 allelic variants.