We report three siblings with neurodevelopmental delays from an Ashkenazi Jewish family with a homozygous variant (p.Ala2Gly) in TRAPPC2L gene, identified by whole genome sequencing. We previously reported another TRAPPC2L variant (p.Asp37Tyr) in two individuals with neurodevelopmental delay plus additional clinical findings. TRAPPC2L encodes a subunit of the conserved TRAPP complexes that functions in transport of vesicles between organelles. Interestingly, functional studies showed different effects of the two variants on TRAPPC2L protein’s interaction with other TRAPP complex subunits, some of which are associated with Mendelian disorders that are now collectively called ‘TRAPPopathies’. Our report strengthens the genetic evidence for TRAPPC2L causing a rare neurodevelopmental disorder with clinical variability and expands the existing knowledge on the TRAPP complex architecture. (https://jmg.bmj.com/content/early/2020/08/25/jmedgenet-2020-107016 )