SIPA1L3 (signal-induced proliferation-associated 1 like 3) is a GTPase-activating protein (GAP) that plays a critical role in epithelial cell morphogenesis, polarity, adhesion, and cytoskeletal organization, particularly in the lens 1. The protein regulates Rap family GTPases through its Rap-GAP domain and is essential for proper eye and lens development 2. SIPA1L3 functions within an Epha4/Sipa1l3/Wnt signaling pathway that controls eye specification and lens fiber cell maturation; loss of either Epha4 or Sipa1l3 results in smaller eyes and lenses due to dysregulated canonical Wnt signaling 3. In neuronal tissue, SIPA1L3/SPAR3 localizes to excitatory postsynapses and interacts with postsynaptic scaffold proteins, suggesting a role in synaptic function 4. Mutations in SIPA1L3 cause autosomal recessive congenital cataracts 2, representing one of the most important causes of blindness in infancy. Pathogenic variants disrupt epithelial cell organization, cell polarity, and adherens junction formation, leading to abnormal epithelial-to-mesenchymal transition in the lens 1. Additionally, SIPA1L3 variants have been identified in association with kidney disease susceptibility 5, suggesting broader physiological roles beyond ocular development.