FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase, responsible for charging mitochondrial tRNA(Phe) with phenylalanine during translation 1. The enzyme catalyzes aminoacylation of mt-tRNAPhe to enable mitochondrial protein synthesis 2. Beyond its canonical function, FARS2 also catalyzes attachment of m-Tyr (oxidized phenylalanine) to tRNA(Phe), potentially delivering ROS-damaged amino acids to mitochondrial ribosomes. FARS2 deficiency impairs mitochondrial homeostasis by blocking mt-tRNAPhe aminoacylation and reducing mitochondrial protein synthesis, ultimately disrupting the mitochondrial quality control system through enhanced mitochondrial hyperfragmentation and disrupted mitophagy 2. Loss of FARS2 function also impairs developmental angiogenesis by reducing mitochondrial respiration and disrupting angiogenic regulatory pathways 3. Pathogenic FARS2 mutations cause multiple severe disorders. Autosomal recessive mutations cause combined oxidative phosphorylation deficiency 14, characterized by early-onset intractable seizures, developmental delay, and encephalopathy 45. FARS2 mutations also cause spastic paraplegia 77, featuring progressive lower limb spasticity from pyramidal tract dysfunction 6. Recently, FARS2 variants were identified as novel cardiomyopathy genes, causing hypertrophic cardiomyopathy with progressive heart failure through mitochondrial dysfunction 2. Disease severity varies, with some compound heterozygous carriers showing slower progression than homozygous patients 7.