Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs.Communicated by Ramaswamy H. Sarma.