The mpox virus (MPXV) is undergoing mutations at an alarmingly rapid pace, necessitating heightened genomic surveillance to manage its global spread. However, current assessments lack a comprehensive evaluation of genomic variations and the influence of environmental and social factors. To address this gap, we developed the mpox virus variations risk evaluation system (VarEPS-MPXV), which uses a multidimensional strategy to assess observed and virtual variations—those that have yet to occur—thereby mitigating time-lag issues in risk prediction. The system integrates six environmental and four social factors to monitor their impact on genomic variation. By analyzing 17,523 publicly available MPXV sequences, we identified 61,788 unique amino acid variants and highlighted five significant mutations. Notably, OPG118: K606E is predicted to play a critical role in MPXV survival and transmission. Our assessment revealed that most key mutations involved amino acid substitutions with low mutational barriers. Variations in the OPG190 gene may alter antibody affinity, while the mutation at site 127 in the OPG038 gene may influence immune protein binding stability. The VarEPS-MPXV offers vital support for managing MPXV outbreaks and other viral diseases, contributing to global public health research and practice. Researchers can freely access the database at https://nmdc.cn/mpox/.