From late March through April 2021, we experienced a cluster of patients with COVID-19, named “Cluster K”, with rapid severe illness compared with those who were infected before. Patients with COVID-19 who were enrolled in this study were divided into two groups: 66 patients from November 2020 to March 2021 (group A) and 37 patients whose infection links were traced from Cluster K (group B). The primary outcome was mortality rate, and the secondary outcome was maximal oxygen flow rate as the severity of the disease. Viral genome sequences were compared between the two groups. Mortality rates were 6.1% in group A and 16.2% in group B (odds ratio: 2.97, 95% confidence interval: 0.65–15.38). The patients in group B required high oxygen flow rate (O2 ≥10 l/min) in the earlier clinical course (P = 0.029). Viral genome sequences revealed five amino acid mutations; of these, four were found on three nonstructural proteins (NSPs): one in nsp3 and nsp15, two in nsp6 (one of them is near the potential sites under positive selective pressure). Another one was on the S protein. This study suggests that mutations in NSPs, especially nsp6, are associated with adverse clinical outcome in patients with COVID-19.