The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has inflicted enormous loss of human lives and devastating economic hardship across the globe. Although several vaccines and medications have been developed and the situation has improved, the seemingly endless mutation of the genome of SARS-CoV-2 and the emergence of new strains of the virus continue to cause grave concerns. In the face of the challenges, one of the questions people often ask is why the virus causes different symptoms and different degrees of harmfulness to different individuals. For example, why do individuals with preexisting conditions such as cancer, diabetes and obesity have more severe symptoms? Currently, these questions are mainly answered in the context of induced immunity in the literature. In addition, answers in contexts such as affinity of ACE2 with spike protein and doses of virus exposed have also been suggested. Further, genome wide association studies have been carried out to answer these questions on the ground of genetics. In this paper, we report our studies on the effects of several RNA modifications (Figure )pseudouridine (Ψ), 5-methylcytosine (m 5 C), N -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), and N 3 -methylcytosine (m 3 C) that can potentially be installed on the SARS-CoV-2 RNA genome by the host epitranscriptomic machinery -on the catalytic activity of SARS-CoV-2 replication complex (SC2RC), which includes RNA dependent RNA polymerase (RdRp). Because viral genome replication and transcription are among the critical steps in the life cycle of viruses, we reasoned that the effect of epitranscriptomics on the activity of SC2RC would provide additional insights on the causes of different severity of symptoms inflicted by SARS-CoV-2 on different individuals.