ALDH18A1

The encoded bifunctional enzyme converts glutamate to glutamate 5-semialdehyde, a critical step in the biosynthesis of proline, ornithine and arginine. Mutations cause cutis laxa (both autosomal dominant and recessive forms) and hereditary spastic paraplegia (types 9A and 9B), with associated features including hyperammonemia, cataracts, and connective tissue abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.52) and exhibits both autosomal dominant and recessive inheritance patterns depending on the specific condition.