RARS1 encodes arginyl-tRNA synthetase 1 (ArgRS), a cytoplasmic enzyme that catalyzes the attachment of arginine to cognate tRNAs during protein synthesis 1. RARS1 functions as a core component of the multi-tRNA synthetase complex (MSC), assembling with AIMPs through leucine zipper motifs to form a structured macromolecular complex 2. Beyond translation, RARS1 modulates secretion of AIMP1 and may regulate generation of the inflammatory cytokine EMAP2 from AIMP1 1. Biallelic RARS1 variants cause hypomyelinating leukodystrophy-9 (HLD-9) and developmental and epileptic encephalopathy (DEE) 3. Disease severity correlates with variant type: truncating variants and those affecting the ArgRS active center cause severe early-onset epilepsy with brain atrophy, while the recurrent c.5A>G mutation produces milder phenotypes 4. Pathogenic variants reduce ArgRS protein stability or activity, impairing translation of ArgRS isoforms 43. Notably, the c.5A>G mutation suppresses mRNA translation through an upstream open reading frame mechanism rather than reducing protein stability 5. Common clinical features include intellectual disability, developmental delay, hypomyelination, nystagmus, and spasticity, with disease onset typically between 0-10 months 6. Beyond white matter effects, RARS1 mutations influence cortical development 3. Genetic screening enables diagnosis in approximately half of patients presenting with hypomyelinating leukoencephalopathy 7.