Potential ORFs were sought in the extended segments of terminal variable regions in the variola virus genome. These ORFs underwent a detailed structural and functional analysis and were compared both between themselves and with homologous ORFs of various orthopoxviruses. The most conservative and heterogeneous ORFs of 70 VARV strains were detected. The unique for VARV ORF (111 a.a) was revealed for Helder and Mary strains of the Russian collection. In addition, only in the Helder strain, ORF D14L was disintegrated into two separate ORFs. A number of ambiguities were found in the current databases for VARV ORF. The dominating type of evolution was ascertained to be stabilizing selection for analyzed ORF. It has been established that VARV ORF C3L, unlike other poxviral orthologs, undergoes an adaptive selection. These findings suggest that this gene plays an important role in human VARV adaptation.