Based on the results with m 1 A modification, one would expect that the m 3 C modification could stop the RNA extension reaction in a similar fashion because m 3 C also disrupts canonic hydrogen bonding, in this case, that of the G-C base pair. However, our results indicate the opposite. The efficiency of the RNA extension reaction was almost the same as the cases of Ψ, m 5 C and m 6 A modifications, in which cases canonic hydrogen bonding was intact. The observation is interesting in the context that m 3 C severely inhibits HIV-1-RT and MMLV-RT. In those instances, less than 5% primers could be extended beyond the modification even though those polymerases are generally considered having low replication fidelity, which would be expected to be more tolerant of modifications. Although more studies are needed to determine which bases are incorporated across m 3 C in the case of SARS-CoV-2 , it is unlikely that the base is G with high fidelity because even modifications such as m 6 A, m 5 C and Ψ that do not disrupt hydrogen bonding of canonic base pairs have been found to increase error rate of some polymerases. Therefore, if the human transcriptomic machinery can indeed install m 3 C onto the SARS-CoV-2 genome, the modification could inactivate the virus via lethal mutagenesis like the antiviral agent Favipiravir does. It could also serve as a driving force for the evolution of the virus given that the modification can survive demethylation enzymes, and some of the mutated genomes are functional. In addition to implications to COVID-19, the finding that m 3 C does not inhibit the SC2RC is also useful for researchers who intend to select polymerases for sequencing studies aimed to identifying m 3 C with single base resolution using the next generation sequencing or nanopore sequencing platforms.