FREM3 is an extracellular matrix protein that plays important roles in basement membrane structure and cellular functions. The protein localizes to epithelial basement membranes, with a broader distribution pattern compared to other FRAS1/Frem family members, being found in various skin and internal epithelial basement membranes where it colocalizes with collagen VII 1. FREM3 functions independently from the mutually stabilized Fras1/Frem1/Frem2 protein complex, contributing to basement membrane biology and epithelial-mesenchymal integrity 2. The gene shows significant clinical relevance through genetic polymorphisms that confer protection against severe malaria, with variants in FREM3 associated with reduced malaria susceptibility in African populations 34. Additionally, FREM3 polymorphisms have been linked to neuropsychiatric phenotypes, including major depressive disorder susceptibility, altered amygdala reactivity, and perceptual processing speed, potentially through effects on gene expression 56. The protein is also implicated in neurodegenerative diseases, with FREM3-expressing neurons being among those most affected by TDP-43 pathology in ALS/ALS-FTD motor cortex 7. These diverse associations suggest FREM3 plays crucial roles in both structural integrity and disease susceptibility across multiple organ systems.