AP4B1 encodes a subunit of the adaptor protein complex 4 (AP-4), a heterotetrameric coat complex that regulates vesicular transport of membrane proteins. AP-4 mediates protein sorting and trafficking from the trans-Golgi network to the endosomal-lysosomal system and controls basolateral protein localization in epithelial cells and somatodendritic protein distribution in neurons. At the population level, gnomAD v4.1 classifies AP4B1 as loss-of-function (LoF) tolerant (LOEUF=0.78); however, the gene harbors 62 pathogenic variants in ClinVar, indicating clinical pathogenicity in specific disease contexts distinct from population-level constraint. Bi-allelic loss-of-function variants in AP4B1 cause spastic paraplegia type 47 (SPG47), a childhood-onset hereditary spastic paraplegia characterized by early developmental delay with prominent motor and speech delay, progressive spasticity, intellectual disability, epilepsy (66% of patients), microcephaly (83%), and distinctive neuroimaging features including corpus callosum thinning and white-matter loss 1. Recent evidence suggests the disorder is more common than previously appreciated, occurring in both consanguineous and non-consanguineous populations 2. Disease severity correlates with early-onset epilepsy, and clinical features are comparable across all four AP-4 subunit mutations, termed 'AP-4 deficiency syndrome' 1. Gene replacement therapy using adeno-associated virus to restore AP4B1 function has demonstrated efficacy in preclinical mouse models, with restoration of motor function and normalization of cargo protein localization, supporting clinical trial development 3.