{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:44:55Z","timestamp":1753875895776,"version":"3.41.2"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>High-throughput DNA sequencing has revealed millions of single nucleotide variants (SNVs) in the human genome, with a small fraction linked to disease. The effect of missense variants, which alter the protein sequence, is particularly challenging to interpret due to the scarcity of clinical annotations and experimental information. While using conservation and structural information, current prediction tools still struggle to predict variant pathogenicity. In this study, we explored the pathogenicity of homologous missense variants\u2014variants in equivalent positions across homologous proteins\u2014focusing on proteins involved in autosomal dominant diseases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our analysis of 2976 pathogenic and 17\u00a0555 non-pathogenic homologous variants demonstrated that pathogenicity can be extrapolated with 95% accuracy within a family, or up to 98% for closer homologs. Remarkably, the evaluation of 27 commonly used mutation predictor methods revealed that they were not fully capturing this biological feature. To facilitate the exploration of homologous variants, we created HomolVar, a web server that computationally predicts the pathogenesis of missense variants using annotations from homologous variants, freely available at https:\/\/rarevariants.org\/HomolVar. Overall, these findings and the accompanying tool offer a robust method for predicting the pathogenicity of unannotated variants, enhancing genotype-phenotype correlations, and contributing to diagnosing rare genetic disorders.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>HomolVar is freely available at https:\/\/rarevariants.org\/HomolVar.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf305","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T15:42:27Z","timestamp":1747237347000},"source":"Crossref","is-referenced-by-count":0,"title":["Missense variants pathogenicity annotation from homologous proteins"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4246-1673","authenticated-orcid":false,"given":"Gabriel","family":"Ruiz-Al\u00edas","sequence":"first","affiliation":[{"name":"Department of Biosciences, Faculty of Sciences and Technology, University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]},{"name":"Institute for Research and Innovation in Life and Health Sciences (IRIS-CC), University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7439-9196","authenticated-orcid":false,"given":"Sergi","family":"Soldevila","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Faculty of Sciences and Technology, University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]},{"name":"Institute for Research and Innovation in Life and Health Sciences (IRIS-CC), University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7595-0647","authenticated-orcid":false,"given":"Xavier","family":"Altafaj","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona , Barcelona 08036,","place":["Spain"]},{"name":"Agust\u00ed Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona , Barcelona 08036,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3848-2928","authenticated-orcid":false,"given":"Arnau","family":"Cordom\u00ed","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Aut\u00f2noma de Barcelona (UAB) , Barcelona 08193,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-3399","authenticated-orcid":false,"given":"Mireia","family":"Olivella","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Faculty of Sciences and Technology, University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]},{"name":"Institute for Research and Innovation in Life and Health Sciences (IRIS-CC), University of Vic-Central University of Catalonia , Vic, Barcelona 08500,","place":["Spain"]}]}],"member":"286","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"2025052922564129400_btaf305-B1","first-page":"1","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"20","author":"Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"2025052922564129400_btaf305-B2","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajhg.2018.08.005","article-title":"ClinPred: 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