Intrinsically disordered regions (IDRs) are abundant in the proteome of RNA viruses. The multifunctional properties of these regions are widely documented and their structural flexibility is associated with the low constraint in their amino acid positions. Therefore, from an evolutionary stand point, these regions could have a greater propensity to accumulate non-synonymous mutations (NS) than highly structured regions (ORs, or ‘ordered regions’). To address this hypothesis, we compared the distribution of non-synonymous mutations (NS), which we relate here to mutational robustness, in IDRs and ORs in the genome of potyviruses, a major genus of plant viruses. For this purpose, a simulation model was built and used to distinguish a possible selection phenomenon in the biological datasets from randomly generated mutations. We analyzed several short-term experimental evolution datasets. An analysis was also performed on the natural diversity of three different species of potyviruses reflecting their long-term evolution. We observed that the mutational robustness of IDRs is significantly higher than that of ORs. Moreover, the substitutions in the ORs are very constrained by the conservation of the physico-chemical properties of the amino acids. This feature is not found in the IDRs where the substitutions tend to be more random. This reflects the weak structural constraints in these regions, wherein an amino acid polymorphism is naturally conserved. In the course of evolution, potyvirus IDRs and ORs follow different evolutive paths with respect to their mutational robustness. These results have forced the authors to consider the hypothesis that IDRs and their associated amino acid polymorphism could constitute a potential adaptive reservoirRead less <