TRAPPC6B encodes a core subunit of the transport protein particle (TRAPP) complex, which regulates inter-organelle membrane trafficking and vesicle tethering 1. The protein is enriched in the TRAPP II complex and plays a specialized role distinct from its homologue TRAPPC6A 1. TRAPPC6B is essential for brain development and neuronal function, likely by controlling intracellular calcium transients that regulate neuron differentiation and survival. Biallelic TRAPPC6B variants cause a severe neurodevelopmental disorder characterized by non-progressive microcephaly, global developmental delay, intellectual disability, epilepsy, and absent expressive language 1. Additional features include movement disorders (stereotypies, spasticity, dystonia) and neuroimaging abnormalities including cortical reduction, cerebellar atrophy, corpus callosum hypoplasia, and white matter changes 1. Disease mechanisms involve impaired Golgi trafficking and fragmentation 1, with evidence from zebrafish models showing decreased head size and neuronal hyperexcitability 2. Pathogenic variants include homozygous nonsense mutations, canonical splice-site variants, and frameshift mutations 1. A TRAPPC6B splicing variant (c.485G>A) has also been associated with restless legs syndrome 3. Beyond neurodevelopment, TRAPPC6B was identified as a novel host factor involved in Shiga toxin trafficking in kidney epithelial cells 4.