Knowing the factors that cause different responses by different individuals to the same virus such as SARS-CoV-2 at the molecular level is important for many reasons. For example, the knowledge can be helpful for the identification of high risk populations, and can be used for the development of medicines. For this reason, questions regarding the differences have been raised frequently since the start of the pandemic. Many answers have been provided. In principle, every step in the life cycle of a virus in human could contribute to the difference because different person provides a different microenvironment for the virus. Even for the same individual, the microenvironment may vary from time to time due to factors such as stress level, medications taken and health conditions. The replication of its RNA genome and transcription of viral mRNAs by SC2RC are critical steps of the life cycle of SARS-CoV-2, and any variations of the step in different individuals could be a factor for the different severity of COVID-19. It is known that RNA genomes are subject to modifications by the human transcriptomic machinery and we believe that the levels of modifications are different for different individuals. Thus, it is logical to hypothesize that epitranscriptomic modifications could affect the efficiency of viral RNA replication and transcription, and the modifications could be among important factors for the difference in severity of the disease.