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The effects of these variants can be captured in disease-specific reactions and pathways that highlight the resulting changes to normal biology. A disease reaction is defined as an aberrant reaction in which a variant protein participates. A disease pathway is defined as a pathway that contains a disease reaction. Annotation of disease variants as participants of disease reactions and disease pathways can provide a standardized overview of molecular phenotypes of pathogenic variants that is amenable to computational mining and mathematical modeling. Reactome (https:\/\/reactome.org\/), an open source, manually curated, peer-reviewed database of human biological pathways, in addition to providing annotations for &amp;gt;11\u2009000 unique human proteins in the context of \u223c15\u2009000 wild-type reactions within more than 2000 wild-type pathways, also provides annotations for &amp;gt;4000 disease variants of close to 400 genes as participants of \u223c800 disease reactions in the context of \u223c400 disease pathways. Functional annotation of disease variants proceeds from normal gene functions, described in wild-type reactions and pathways, through disease variants whose divergence from normal molecular behaviors has been experimentally verified, to extrapolation from molecular phenotypes of characterized variants to variants of unknown significance using criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Reactome\u2019s data model enables mapping of disease variant datasets to specific disease reactions within disease pathways, providing a platform to infer pathway output impacts of numerous human disease variants and model organism orthologs, complementing computational predictions of variant pathogenicity.<\/jats:p>\n                  <jats:p>Database URL: https:\/\/reactome.org\/<\/jats:p>","DOI":"10.1093\/database\/baae031","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T02:28:07Z","timestamp":1711938487000},"source":"Crossref","is-referenced-by-count":4,"title":["Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes"],"prefix":"10.1093","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3218-5631","authenticated-orcid":false,"given":"Marija","family":"Orlic-Milacic","sequence":"first","affiliation":[{"name":"Adaptive Oncology, Ontario Institute for Cancer Research , 661 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Hinxton, Cambridgeshire CB10 1SD, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-6503","authenticated-orcid":false,"given":"Eliot","family":"Ragueneau","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8674-1739","authenticated-orcid":false,"given":"Chuqiao","family":"Gong","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus , Hinxton, Cambridgeshire CB10 1SD, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4650-631X","authenticated-orcid":false,"given":"Ralf","family":"Stephan","sequence":"additional","affiliation":[{"name":"Adaptive Oncology, Ontario Institute for Cancer Research , 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada"},{"name":"Institute for Globally Distributed 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