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This is particularly relevant for genes with many variants of unknown significance (VUS), such as\n                  <jats:italic>PRPH2<\/jats:italic>\n                  -retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Plain Language Summary<\/jats:title>\n                  <jats:p>Distinguishing disease-causing mutations from benign ones remains a major barrier to precision medicine. Here, the authors combine AI-generated protein structures with clinical data and expert human adjudication to show that where a PRPH2 variant sits in three-dimensional space predicts the specific retinal disease it causes, enabling variant prioritization for gene-therapy trials<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.10.07.26364649","type":"posted-content","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:15:19Z","timestamp":1791562519000},"source":"Crossref","is-referenced-by-count":0,"title":["Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis"],"prefix":"10.64898","author":[{"given":"Young Joo","family":"Sun","sequence":"first","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Velez","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Li","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarushi","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer T.","family":"Vu","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Phillips","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ditte K.","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA"},{"name":"Department of Biomedicine, Aarhus University, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Kyun","family":"Oh","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Pathology & Cell Biology, Columbia Stem Cell Initiative, Vagelos College of Physicians & Surgeons, New York, NY, USA"},{"name":"Jonas Children\u2019s Vision Care, Edward S. Harkness Eye Institute, New York Presbyterian Hospital, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio G. S.","family":"Costa","sequence":"additional","affiliation":[{"name":"Programa de Computa\u00e7\u00e3o Cient\u00edfica, Vice-Presid\u00eancia de Educa\u00e7\u00e3o Informa\u00e7\u00e3o e Comunica\u00e7\u00e3o, Funda\u00e7\u00e3o Oswaldo Cruz, Riode Janeiro, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen H.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Pathology & Cell Biology, Columbia Stem Cell Initiative, Vagelos College of Physicians & Surgeons, New York, NY, USA"},{"name":"Jonas Children\u2019s Vision Care, Edward S. 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