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Increasing evidence suggests that intrinsically disordered proteins and regions (IDPs\/IDPRs), which lack a stable three-dimensional structure, are significant in disease pathology due to their flexible nature, impacting protein interactions and function. This study explores the intrinsic disorder within CYP1B1 and its implications in the molecular mechanisms underlying PCG. We employed a comprehensive bioinformatics approach to assess the structural and functional properties of CYP1B1 using tools such as AlphaMissense, a tool crafted to evaluate the functional impact of missense mutations in proteins. Our structural analysis qualitatively demonstrated that CYP1B1 contains intrinsically disordered protein regions (i.e., spaghetti-like entities) that are structureless and flexible. Correlation analysis showed that disorder decreases exponentially relative to AlphaMissense predicted pathogenicity, with an exponential decay fit (<jats:italic>R<\/jats:italic>\n            <jats:sup>2<\/jats:sup> = 0.62), suggesting that highly disordered regions tend to harbor benign mutations. This study identifies critical intrinsically disordered regions within CYP1B1 and elucidates its complex interaction network, highlighting the potential role of these regions in PCG pathogenesis. The observed correlation between intrinsic disorder and reduced pathogenicity of mutations suggests that IDPRs may buffer against deleterious effects, providing a possible explanation for the variability in clinical outcomes associated with CYP1B1 mutations. These insights enhance our understanding of the molecular basis of PCG and offer potential targets for novel therapeutic interventions to combat this blinding childhood disorder.  <\/jats:p>","DOI":"10.1007\/s42485-025-00186-8","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T10:53:28Z","timestamp":1747133608000},"page":"347-361","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intrinsic disorder in CYP1B1 and its implications in primary congenital glaucoma pathogenesis"],"prefix":"10.1007","volume":"16","author":[{"given":"Meghan","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Taylor","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Antonietti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Uversky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mak","family":"Djulbegovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"186_CR1","first-page":"1","volume":"1","author":"J Abramson","year":"2024","unstructured":"Abramson J et al (2024) Accurate structure prediction of biomolecular interactions with AlphaFold 3. 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