One method that can help slow the spread of coronaviruses is disinfection with UV light. The Delta and Omicron variants of the COVID-19 virus (SARS-CoV-2) have come to dominate the later stages of the pandemic due to their higher rates of transmission. In this work, it is shown that a 17% higher UV 254 dose is required for the disinfection of Delta and Omicron variants when compared to the ancestral strain of SARS-CoV-2. The UV 254 disinfection rate constants for SARS-CoV-2 and the Delta and Omicron variants were found to be 1.4 ± 0.3, 1.1 ± 0.2, and 1.1 ± 0.2 cm 2 /mJ, respectively. The rate constants of Delta and Omicron were statistically different from the ancestral strain of SARS-CoV-2 at the 95% confidence level based on at least three replicate experiments. It is suggested that the reason for this difference is the absence of repeating uracil (U) bases in the genome of the two variants. The UV 254 sensitivity of repeating pyrimidine bases is well-established. There are 2.6 and 3.7% fewer uracil triplets (UUU) in the Delta and Omicron variants, respectively, when compared to SARS-CoV-2. This difference in UV 254 sensitivity is relevant to a range of UV disinfection applications including upper-room disinfection, air handling equipment, aircraft sanitization, and others.