Mutations within the olfactomedin domain of myocilin (OLF) cause cytotoxic amyloid-like aggregation in the endoplasmic reticulum in cells of the anterior eye segment, which in turn hasten the progression of vision loss due to glaucoma. Despite progress in molecular characterization of OLF at a molecular level, structural perturbations introduced by pathogenic mutations has remained unclear. I will present recent findings from my lab on the emerging relationship between wild-type and mutant OLF unfolding and aggregation. Our data indicate that conformational changes required to promote fibrillization for wild-type OLF and the non-native structure adopted by disease variants are on pathway to OLF unfolding. More broadly, our study illustrates complexities introduced by large amyloid-forming proteins when undergoing folded-to-misfolded transitions compared to smaller model amyloid systems.