TRIM74 is a tripartite motif-containing ubiquitin ligase located on chromosome 7 that functions in protein homeostasis and quality control 1. As an E3 ubiquitin ligase family member 2, TRIM74 participates in ubiquitination pathways and transcriptional regulation essential for maintaining neuronal integrity 1. The gene evolved through segmental duplication events in primates, with TRIM74 arising as a duplicated copy of TRIM50 containing five exons rather than the original seven 3. Pathogenic mutations in TRIM74 disrupt protein folding and stability, triggering proteotoxic neurodegeneration. A homozygous missense variant (p.Pro121Leu) caused structural destabilization, increased protein aggregation, cytosolic accumulation, and elevated proteotoxic stress in patient-derived cells, manifesting as global developmental delay, seizures, and cerebral atrophy 1. TRIM74 expression is highest in the cerebellum and medulla, consistent with observed neurological involvement 1. Clinically, TRIM74 dysregulation associates with disease progression in nasopharyngeal carcinoma, where upregulation correlates with distant metastasis and poor disease-free survival 4. Additionally, rare pathogenic variants in TRIM74 have been identified in syndromic orofacial clefts with limb abnormalities, suggesting developmental roles beyond neuronal function 5.