{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T08:58:39Z","timestamp":1773133119667,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG\/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework\u2019s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.<\/jats:p>","DOI":"10.64898\/2026.03.05.26347086","type":"posted-content","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T19:30:19Z","timestamp":1772825419000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2591-432X","authenticated-orcid":false,"given":"Tobias","family":"Br\u00fcnger","sequence":"first","affiliation":[{"name":"Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"name":"Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilona","family":"Krey","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Kl\u00f6ckner","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott J","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare 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