POLG encodes the catalytic subunit of mitochondrial DNA polymerase gamma, the sole polymerase responsible for replication of the mitochondrial genome. The enzyme replicates both strands of circular mtDNA by incorporating deoxyribonucleoside triphosphates using a single-stranded DNA template and RNA primers, functioning as part of a highly processive replisome complex with the helicase TWNK and single-strand binding protein SSBP1. POLG possesses both 5'→3' polymerase activity and 3'→5' exonucleolytic proofreading activity, enabling high-fidelity replication and base mismatch correction; it also catalyzes 5'-deoxyribose phosphate lyase activity to support base-excision repair and gap-filling synthesis. POLG mutations are the most common cause of inherited mitochondrial disorders, responsible for a spectrum of phenotypes including Alpers-Huttenlocher syndrome, progressive external ophthalmoplegia, myoclonic epilepsy myopathy sensory ataxia, and ataxia neuropathy spectrum 1. These mutations lead to mtDNA depletion or multiple deletions, causing multi-organ neurological disease often with onset from infancy to adulthood 2. Status epilepticus occurs in approximately two-thirds of patients with POLG disease and carries high mortality risk 3. At the population level, gnomAD v4.1 classifies this gene as loss-of-function tolerant (LOEUF=0.85); this is distinct from clinical pathogenicity, as 373 ClinVar variants are classified as pathogenic or likely pathogenic. Recent therapeutic advances include small-molecule activators such as PZL-A that restore function to common POLG mutant variants in patient-derived cells 4, and clofilium tosylate has shown partial rescue of mtDNA depletion in preclinical models 5.