HARS1 (histidyl-tRNA synthetase 1) catalyzes the ATP-dependent ligation of histidine to its cognate tRNA via formation of a His-AMP intermediate, a critical step in cytoplasmic protein translation 1. Beyond its canonical role in aminoacylation, HARS1 plays a role in axon guidance 2. Pathogenic HARS1 variants cause disease through a dominant-negative mechanism. CMT-associated HARS1 mutations (V155G, Y330C, R137Q) attenuate protein synthesis, increase eIF2α phosphorylation, and impair neurite outgrowth in neuronal models and developing zebrafish 34. Mutant HARS1 proteins form heterodimers with wild-type enzyme, disrupting normal function 3. The D364Y mutation causes protein aggregation and inhibits neuronal process formation, effects reversible by valproic acid 5. Clinically, HARS1 mutations associate with autosomal-dominant Charcot-Marie-Tooth disease type 2W (CMT2W) and autosomal-recessive Usher syndrome type 3B 6. HARS1 variants appear in approximately 1.22% of CMT patients 6. Bi-allelic mutations cause a novel multisystem ataxic syndrome with severely impaired HARS1 expression and enzymatic activity 7. Pathogenic variants also occur in ALS patients at lower frequency 8.