Background <p>Coronavirus disease 2019 (COVID-19) has been a challenging pandemic since late 2019 and patients with COVID-19-related severe respiratory failure associated with high mortality rates worldwide. Genetic information such as single nucleotide polymorphisms (SNPs) serves as a predictor or prognostic factor in disease development and cancer progression. This study aimed to explore the clinical associations of SNPs with mild and severe COVID-19 symptoms in the Taiwanese population.</p> Methods <p>SARS-CoV-2-infected patients in pilot cohort study (cohort 1, <i>n</i> = 39) and validation cohort (cohort 2, <i>n</i> = 71) were enrolled. The clinical significance of SNPs in those patients with mild and severe symptoms was investigated by whole exon sequencing, polymerase chain reaction and Sanger sequencing.</p> Results <p>The current study investigated Taiwanese patients with COVID-19. We found that clinical parameters such as age, aspartate aminotransferase, blood urea nitrogen, C-reactive protein, ferritin, and segment were positively associated with severe COVID-19 symptoms but that albumin, lymphocytes, and basophils correlated negatively with severe symptoms in two independent cohorts. By conducting whole-exome sequencing, we identified a novel SNP, ZNF717-rs2918520, the GG genotype of which was significantly associated with severe symptoms in COVID-19 patients.</p> Conclusions <p>Our findings highlight that the ZNF717-rs2918520 GG genotype may serve as a predictor for evaluating the severity of COVID-19 in Taiwan.</p>