ACSF3 encodes a mitochondrial acyl-CoA synthetase that catalyzes activation of malonate and methylmalonate to their CoA thioesters, with substrate preference toward very-long-chain fatty acids. The enzyme plays a critical metabolic role by generating malonyl-CoA within the mitochondrial matrix, thereby clearing malonate—a potent inhibitor of succinate dehydrogenase—and enabling its conversion to acetyl-CoA 1. ACSF3-derived malonyl-CoA can also malonylate mitochondrial proteins, providing post-translational regulatory control 1. Biallelic ACSF3 variants cause combined malonic and methylmalonic acidemia (CMAMMA), an inborn error of metabolism characterized by elevated urinary malonic and methylmalonic acids 2. While early descriptions emphasized benign presentations with normal developmental outcomes, recent evidence expands the clinical spectrum: some patients develop severe developmental and epileptic encephalopathy with refractory seizures, autism, and intellectual disability 3. ACSF3 variants have also been detected in association with other multisystem disorders including global developmental delay and skeletal abnormalities 4. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant (LOEUF=1.72); however, 186 pathogenic/likely pathogenic ClinVar variants demonstrate distinct clinical pathogenicity in disease contexts. Recent evidence suggests that an ancient regulatory variant, rs34590044-A, upregulates ACSF3 and may have facilitated human adaptation to meat-enriched diets, contributing to increased height and basal metabolic rate 5.