The alphaherpesvirus Varicella-Zoster Virus (VZV) infects most humans. It causes chickenpox, shingles and rare severe central nervous system (CNS) pathologies. To gain molecular insights in the virus’ pathobiology, we conducted a proteomic survey on the interactions and effects of 64 VZV proteins, and VZV infection-induced perturbations, in neuronal SK-N-BE2 cells. This identified 900 interactors and 3618 regulated host proteins (https://varizonet.innatelab.org). Data integration and functional validations of the identified host proteins unveiled NPHP4 as VZV restriction factor. Combining whole exome of patients with VZV-associated CNS pathologies identified the NPHP4 S862N variant. Importantly, the S862N mutation impaired NPHP4's antiviral activity, and supressed its interactions with 14-3-3 proteins, as measured by affinity-purification.