Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA) is a childhood-onset neurodevelopmental disorder with multi-organ manifestations, including recurrent infections. It is caused by variants in NHLRC2, initiating a cascade of unknown pathological events. We investigated the FINCA disease-causing p.Asp148Tyr variant in NHLRC2 by analysing transcriptional changes in mouse embryonic stem cells (mESCs). We conducted behavioural and immunological phenotyping of FINCA mice compound heterozygous for the Nhlrc2 knockout allele and p.Asp148Tyr variant and explored their T cell populations and cytokine production in splenocytes. Additionally, we employed proximity-labelling mass spectrometry to identify changes in protein-protein interactions resulting from the p.Asp148Tyr variant in human embryonic kidney cells. We discovered significant transcriptional changes in mESCs homozygous for the p.Asp148Tyr variant or Nhlrc2 knockout allele compared to wild-type cells, with genes involved in cell metabolism, adhesion, neurodevelopment and immune response. FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells, we identified Rho GTPase signalling as a common affected pathway. Our study provides insights into the molecular pathways impacted by the p.Asp148Tyr NHLRC2. The FINCA mouse, which recapitulates several features of the human condition, particularly neurodevelopmental and immune response defects, serves as a tool for investigations on the role of environmental triggers in disease pathogenesis. Our results suggest that targeting immune pathways could offer a strategy for therapeutic intervention in FINCA disease.