Background The E71G mutation in GARS results in Charcot-Marie-Tooth disease type 2D (CMT2D) with overlapping distal hereditary motor neuropathy type 5A (HMN5A) phenotype, but the pathogenesis is unclear. This study aimed to predict the structural and functional effects of this mutation on GARS’ interaction with some of its putative or actual ligands in relation to CMT2D and HMN5A manifestation. Methods Putative or actual ligands of GARS were identified from 10 protein databases using Cytoscape 3.4.0. Thirty-one (31) ligands met our criteria and were selected for the study. GRAMM-X was utilized for docking simulations. The RMSD value difference between wild-type and docked ligands, change in binding free energy, and changes in interface between wild type and native GARS were analyzed. Results Our in silico analysis showed that GARS interaction with 19 distinct putative or actual ligands increased in stability, 10 decreased in stability, and two (2) were unchanged energetically. Data mining and network analysis showed that the ligands are involved in apoptosis, autophagy, and immune response, as well as the ubiquitin proteasome system and NGF/TrkA signaling. Conclusions These findings indicate that several biological processes (apoptosis, autophagy, and immune response) and pathways (ubiquitin proteasome system and NGF/TrkA signaling) may be affected by the E71G mutation. This suggests that GARS is a key molecule in CMT2D and HMN5A pathogenesis and shows promise as a target for novel drugs. Further experimentation is needed to verify these findings.