CA5A encodes mitochondrial carbonic anhydrase VA, a zinc metalloenzyme that catalyzes the reversible conversion of CO2 to bicarbonate (HCO3−) 1. Since mitochondria are impermeable to HCO3−, CA5A is essential for providing this substrate to four key mitochondrial metabolic enzymes: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched-chain amino acid catabolism) 12. CA5A is most highly expressed in liver and primarily supports ammonia detoxification 3. Biallelic CA5A mutations cause carbonic anhydrase VA deficiency (OMIM #615751), a rare autosomal recessive inborn error of metabolism presenting as life-threatening early-onset hyperammonemia, hyperlactatemia, ketonuria, and metabolic acidosis 21. Clinical mutations demonstrate reduced enzymatic activity and thermal sensitivity 1. The condition is treatable with N-carbamyl-L-glutamate or carglumic acid, which can resolve hyperammonemia and prevent neurological sequelae 31. CA5A deficiency appears more common than other rare metabolic diseases, with higher carrier frequencies in specific populations 4. Beyond metabolic disease, CA5A expression changes have been detected in non-small-cell lung cancer and COVID-19-associated adipose tissue alterations 56.