CCDC88C (coiled-coil and HOOK domain protein 88C) is a guanine nucleotide exchange factor essential for non-canonical Wnt signaling and neural development. Mechanistically, CCDC88C binds ligand-activated Frizzled-7 (FZD7) receptors and displaces DVL1, inhibiting canonical Wnt signaling while activating Gi-alpha subunits to promote non-canonical responses including RAC1 and PI3K-AKT pathway activation 1. Additionally, CCDC88C promotes apical cell constriction through ARHGEF18 2 and participates in neuronal migration and structural brain connectivity 3. Disease relevance is substantial: CCDC88C variants cause congenital hydrocephalus (autosomal recessive) 4, focal epilepsy with predominantly missense mutations conferring favorable outcomes 5, and spinocerebellar ataxia type 40 (SCA40) through splice-site mutations 6. Clinically, CCDC88C expression correlates with CD4+ T cell activation in lung adenocarcinoma via Wnt pathway regulation 7, and dysregulation appears as a biomarker for SCA3/MJD disease progression 8. CCDC88C-PDGFRB fusion proteins in myeloid neoplasms demonstrate imatinib sensitivity 9. The genotype-phenotype correlation suggests truncating mutations cause congenital hydrocephalus while missense variants associate with later-onset epilepsy and ataxia, reflecting critical domain-specific functions.