Synthetic virology is an important multidisciplinary scientific field, with emerging applications in biotechnology and medicine, aiming at developing methods to generate and engineer synthetic viruses. Many viruses of the Flaviviridae family, including the Zika virus (ZIKV) and hepatitis C virus (HCV), are widespread pathogens of significant importance to human health. Yet, there are currently no approved vaccines available for these viruses. Therefore, designing attenuated synthetic versions of these viruses and controlling their virulence is a fundamental milestone in the continuing efforts for dealing with the diseases they cause. Specifically, this approach should help improve our understanding of the genomes of these viruses and may promote developing potential vaccines and virus based therapies. Here we suggest a computational based pipeline for the rational design of attenuated synthetic RNA viruses. Specifically, we generated dozens of synthetic ZIKV and HCV variants based on procedures that preserve viral amino acid content, but affect functional silent aspects of their genome. Preliminary results in ZIKV show significant variant attenuation in Vero cells, which is correlative with our model predictions.