The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) causes a global pandemic named COVID-19. That virus causes a range of human respiratory tract infections; that severity varies from relatively mild to severe respiratory injury syndrome. It has indicated that some individuals might offer susceptibility to SARS‐CoV‐2 infection due to genetic factors. ACE2, TMPRSS2, TYK2, SLC6A20, and IFNAR2 human genes are involved in the pathogenesis of coronavirus in various populations and geographic territories; Therefore, examining the genetic variants of these genes can determine their association with the severity of the COVID-19 disease. In this study, the Whole-Exome Sequencing (WES) technique was used to identify variants of the mentioned human genes concerning the presence or absence of SARS‐CoV‐2 infection in the cohort of 100 individuals from Iran; that may modulate viral infectivity and make some individuals more vulnerable than others. Next, the frequency of variants found in the Iranian population was compared with those belonging to reference individuals from the 1000 Genomes Project, genomAD, and ExAC. In addition, due to the extraordinary importance of the protein’s three-dimensional structure in maintaining the optimal function of the protein, also protein modeling was performed for the essential found variants. The ACE2 gene showed a high level of polymorphism. While TMPRSS2 is less polymorphic. The variants rs759499720/ACE2، rs776459296/ACE2، rs386818798/TMPRSS2، rs771922681/TYK2، rs753470142/TYK2، c.675G>T/TYK2، rs147760034/SLC6A20، rs139008024/SLC6A20, and rs759744926/IFNAR2 showed a significant association with SARS-CoV-2 infection and COVID-19. These variants have previously been detected in studies.