Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare neurological disease caused by mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2) which possibly result in loss of the protein. Beside its potential role in autophagy, TECPR2 may serve as positive modulator of COPII-mediated ER export. However, the molecular consequences of TECPR2 deficiency for the secretory pathway remain unclear, in particular with regard to specific cargo proteins. By employing spatial proteomic approaches, we unveiled pronounced changes in several steps along the secretory pathway with numerous proteins important for neuronal function being affected in their intracellular trafficking or secretion upon loss of TECPR2. Moreover, TECPR2’s associations with endomembranes and components of the secretory pathway were strongly reduced when a HSAN9 mutant TECPR2 variant was expressed. Collectively, this resource provides the first systemic profiling of global secretory pathway defects in a loss of function HSAN9 cell model.