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Background: Health and economies are both affected by the coronavirus disease-19 (COVID-19) global pandemic. Angiotensin-converting enzyme 2 ( ACE2 ) is a polymorphic enzyme that is a part of the renin-angiotensin system, and it plays a crucial role in viral entry. Previous investigations and studies revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ACE2 have a considerable association. Recently, ACE2 variants have been described in human populations in association with cardiovascular and pulmonary conditions. In this study, genetic susceptibility to COVID-19 in different populations was investigated., Methods and Results: We evaluated the identified variants based on the predictive performance of 5 deleteriousness-scoring methods and the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicated 299 variants within the ACE2 gene. The variants were analyzed by different in-silico analysis tools to assess their functional effects. Ultimately, 5 more deleterious variants were found in the ACE2 gene., Conclusions: Collecting more information about the variations in binding affinity between SARS-CoV-2 and host-cell receptors due to ACE2 variants leads to progress in treatment strategies for COVID-19. The evidence accumulated in this study showed that ACE2 variants in different populations may be associated with the genetic susceptibility, symptoms, and outcome of SARS-CoV-2 infection., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Taravat Talebi et al.)