Systematic mapping of O-GlcNAc transferase and O-GlcNAcase defines disease-associated variants

For decades, O-GlcNAcylation has been recognized as a critical post-translational modification involved in numerous physiological processes and increasingly implicated in human disease. Despite substantial evidence linking O-GlcNAcylation to neurodegeneration and cancer, O-GlcNAc cycling enzymes were long considered so essential that any meaningful amino acid substitution would not be tolerated in humans. However, advances in genetic screening have recently identified viable single-nucleotide variants (SNVs) in O-GlcNAc Transferase (OGT) in individuals with X-linked intellectual disability (OGT-XLID). The growing identification of affected families prompted a reevaluation of how subtle genomic variation in O-GlcNAc enzymes contributes to human pathology. Here, we present the first comprehensive catalog of variants in both OGT (oglcnac.mcw.edu/ogtoga/ogt/) and O-GlcNAcase (OGA) (oglcnac.mcw.edu/ogtoga/oga/), the two enzymes that regulate O-GlcNAcylation. This resource integrates cancer-associated mutations, population allele frequencies, and structural mapping onto both protein structures. Recognizing that public repositories such as ClinVar and gnomAD capture only a portion of clinically relevant variation, we partnered directly with clinicians and researchers to curate the most comprehensive and up-to-date collection of pathogenic OGT-XLID variants (n=101). By combining population datasets with cancer mutation databases, we identify distinct hotspot mutations with opposing clinical associations: OGT hotspot mutations correlate with improved survival in cancer patients, whereas OGA hotspot mutations are associated with reduced overall survival. Together, this resource establishes a framework for understanding genotype-phenotype relationships in O-GlcNAc biology and provides a foundation for future mechanistic, translational, and clinical investigations.