PACS1 (phosphofurin acidic cluster sorting protein 1) is a coat protein mediating protein trafficking in the secretory pathway. It localizes trans-Golgi network (TGN) membrane proteins containing acidic cluster sorting motifs by linking their cytoplasmic domains to AP-1 adapter complexes, controlling endosome-to-Golgi trafficking of cargo proteins including furin and mannose-6-phosphate receptors 1. Beyond trafficking functions, PACS1 acts as an HDAC6 effector protein in neurons; the pathogenic Arg203Trp substitution aberrantly increases PACS1/HDAC6 interaction, reducing α-tubulin and cortactin acetylation and causing Golgi fragmentation, dendritic overgrowth with reduced spine density and impaired synaptic transmission 2. PACS1 is essential for ER calcium handling in lymphocytes through a complex with WDR37, maintaining lymphocyte quiescence and survival 3. Pathogenic PACS1 variants cause Schuurs-Hoeijmakers syndrome (SHMS), a rare neurodevelopmental disorder characterized by intellectual disability, distinctive craniofacial features (hypertelorism, thick eyebrows, downslanting palpebral fissures), seizures, and congenital anomalies 4. The recurrent p.Arg203Trp variant is diagnostic for SHMS, while other variants disrupting adaptor protein binding also cause overlapping phenotypes 5. PACS1 mutations share phenotypic overlap with WDR37 and PACS2 variants, suggesting functional convergence in neurodevelopment and ocular development 6. PACS1- and HDAC6-targeting therapies restore neuronal structure in PACS1 syndrome models, offering therapeutic potential 2.