{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:44:25Z","timestamp":1789497865349,"version":"build-2803163510"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM133552"],"award-info":[{"award-number":["R35 GM133552"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM065086"],"award-info":[{"award-number":["T32 GM065086"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL167046"],"award-info":[{"award-number":["R01 HL167046"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R00 HL151965"],"award-info":[{"award-number":["R00 HL151965"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["OLIVER22A0-KB"],"award-info":[{"award-number":["OLIVER22A0-KB"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F31 HL162483"],"award-info":[{"award-number":["F31 HL162483"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Variants in the cystic fibrosis transmembrane conductance regulator gene (\n                    <jats:italic>CFTR<\/jats:italic>\n                    ) result in cystic fibrosis\u2013a lethal autosomal recessive disorder. Missense variants that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis variants, yet tools for accurately predicting molecular consequences of missense variants have been limited to date. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense variants based on dual learned protein structure and evolutionary features. Here, we evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from the CFTR2.org database. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    infection rate. Correlation was also modest with CFTR trafficking and folding competency\n                    <jats:italic>in vitro<\/jats:italic>\n                    . By contrast, the AM score correlated well with CFTR channel function\n                    <jats:italic>in vitro<\/jats:italic>\n                    \u2013demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e.,\n                    <jats:italic>theratype<\/jats:italic>\n                    . Development of new approaches to differentiate the biochemical and pharmacological properties of CFTR variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0297560","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T13:35:02Z","timestamp":1706189702000},"page":"e0297560","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0572-330X","authenticated-orcid":true,"given":"Eli Fritz","family":"McDonald","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-7006","authenticated-orcid":true,"given":"Kathryn E.","family":"Oliver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Schlebach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-193X","authenticated-orcid":true,"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4363-6116","authenticated-orcid":true,"given":"Lars","family":"Plate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,1,25]]},"reference":[{"issue":"7","key":"pone.0297560.ref001","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/0092-8674(93)90353-R","article-title":"Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis","volume":"73","author":"MJ Welsh","year":"1993","journal-title":"Cell"},{"issue":"4922","key":"pone.0297560.ref002","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA","volume":"245","author":"JR Riordan","year":"1989","journal-title":"Science"},{"issue":"1","key":"pone.0297560.ref003","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrg3849","article-title":"Cystic fibrosis genetics: from molecular understanding to clinical application","volume":"16","author":"GR Cutting","year":"2015","journal-title":"Nat Rev Genet"},{"key":"pone.0297560.ref004","article-title":"CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine","author":"EF McDonald","year":"2023","journal-title":"ACS Chem Biol"},{"key":"pone.0297560.ref005","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.coph.2017.09.018","article-title":"Transformative therapies for rare CFTR missense alleles","volume":"34","author":"KE Oliver","year":"2017","journal-title":"Curr Opin Pharmacol"},{"issue":"1","key":"pone.0297560.ref006","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jcf.2018.05.004","article-title":"CFTR modulator theratyping: Current status, gaps and future directions","volume":"18","author":"JP Clancy","year":"2019","journal-title":"J Cyst Fibros"},{"issue":"10","key":"pone.0297560.ref007","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1177\/1087057115605834","article-title":"Facilitating Structure-Function Studies of CFTR Modulator Sites with Efficiencies in Mutagenesis and Functional Screening","volume":"20","author":"SV Molinski","year":"2015","journal-title":"SLAS Discov"},{"key":"pone.0297560.ref008","unstructured":"CF Foundation Patient Registry, https:\/\/www.cff.org\/medical-professionals\/patient-registry. 2022."},{"issue":"19","key":"pone.0297560.ref009","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor\u2013Tezacaftor\u2013Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"PG Middleton","year":"2019","journal-title":"N Engl J Med"},{"issue":"14","key":"pone.0297560.ref010","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1080\/14656566.2023.2230129","article-title":"The revolution of personalized pharmacotherapies for cystic fibrosis: what does the future hold?","volume":"24","author":"KE Oliver","year":"2023","journal-title":"Expert Opin Pharmacother"},{"key":"pone.0297560.ref011","unstructured":"Trikafta Prescribing Information. 2023."},{"issue":"23","key":"pone.0297560.ref012","doi-asserted-by":"crossref","first-page":"7813","DOI":"10.1007\/s00018-021-03994-5","article-title":"Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR","volume":"78","author":"N Baatallah","year":"2021","journal-title":"Cell Mol Life Sci"},{"issue":"1","key":"pone.0297560.ref013","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.cell.2021.12.009","article-title":"Mechanism of CFTR correction by type I folding correctors","volume":"185","author":"K Fiedorczuk","year":"2022","journal-title":"Cell"},{"issue":"6617","key":"pone.0297560.ref014","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1126\/science.ade2216","article-title":"Molecular structures reveal synergistic rescue of \u0394508 CFTR by Trikafta modulators","volume":"378","author":"K Fiedorczuk","year":"2022","journal-title":"Science"},{"key":"pone.0297560.ref015","article-title":"Mechanism of dual pharmacological correction and potentiation of human CFTR","author":"C Wang","year":"2022","journal-title":"Biophysics"},{"key":"pone.0297560.ref016","article-title":"Diagnostic challenges in CFTR-related metabolic syndrome: Where the guidelines fall short","author":"EF Kallam","year":"2023","journal-title":"Paediatr Respir Rev"},{"issue":"5","key":"pone.0297560.ref017","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.jcf.2020.11.006","article-title":"Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome\/cystic fibrosis screen positive, inconclusive diagnosis (CRMS\/CFSPID)","volume":"20","author":"J Barben","year":"2021","journal-title":"J Cyst Fibros"},{"issue":"6","key":"pone.0297560.ref018","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.jcf.2019.04.010","article-title":"Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international 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VX-445 on the plasma membrane expression of clinical","volume":"30","author":"AG McKee","year":"2023","journal-title":"CFTR variants. 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Moving forward","volume":"21","author":"A Hatton","year":"2022","journal-title":"J Cyst Fibros"},{"issue":"9","key":"pone.0297560.ref039","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1038\/s41588-023-01465-0","article-title":"Genome-wide prediction of disease variant effects with a deep protein language model","volume":"55","author":"N Brandes","year":"2023","journal-title":"Nat Genet"},{"issue":"7883","key":"pone.0297560.ref040","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41586-021-04043-8","article-title":"Disease variant prediction with deep generative models of evolutionary data","volume":"599","author":"J Frazer","year":"2021","journal-title":"Nature"},{"issue":"8","key":"pone.0297560.ref041","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/prot.25496","article-title":"Comprehensive mapping of cystic fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site","volume":"86","author":"SV Molinski","year":"2018","journal-title":"Proteins Struct Funct Bioinforma"},{"issue":"4S2","key":"pone.0297560.ref042","first-page":"1","article-title":"Registro italiano Fibrosi Cistica (RIFC). Rapporto 2019\u20132020","volume":"46","author":"G Campagna","year":"2022","journal-title":"Epidemiol Prev"},{"issue":"3","key":"pone.0297560.ref043","doi-asserted-by":"crossref","first-page":"00856","DOI":"10.1183\/23120541.00856-2020","article-title":"Cystic fibrosis in South Africa: spectrum of disease and determinants of outcome","volume":"7","author":"M Zampoli","year":"2021","journal-title":"ERJ Open Res"},{"issue":"10","key":"pone.0297560.ref044","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1016\/j.gim.2022.06.009","article-title":"CFTR genotype analysis of Asians in international registries highlights disparities in the diagnosis and treatment of Asian patients with cystic fibrosis","volume":"24","author":"S Vaidyanathan","year":"2022","journal-title":"Genet Med"},{"issue":"1","key":"pone.0297560.ref045","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/hmg\/1.1.11","article-title":"Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation","volume":"1","author":"CT Jones","year":"1992","journal-title":"Hum Mol Genet"},{"issue":"1","key":"pone.0297560.ref046","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s42003-022-03302-2","article-title":"Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold","volume":"5","author":"F Angl\u00e8s","year":"2022","journal-title":"Commun Biol"},{"issue":"1\u20132","key":"pone.0297560.ref047","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.cell.2011.11.023","article-title":"Requirements for efficient correction of \u0394f508 CFTR revealed by analyses of evolved sequences","volume":"148","author":"JL Mendoza","year":"2012","journal-title":"Cell"},{"issue":"1\u20132","key":"pone.0297560.ref048","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cell.2011.11.024","article-title":"Correction of Both NBD1 Energetics and Domain Interface Is Required to Restore \u0394F508 CFTR Folding and Function","volume":"148","author":"WM Rabeh","year":"2012","journal-title":"Cell"},{"issue":"10","key":"pone.0297560.ref049","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1002\/pro.479","article-title":"Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1","volume":"19","author":"I Protasevich","year":"2010","journal-title":"Protein Sci"},{"issue":"8","key":"pone.0297560.ref050","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1096\/fj.09-141788","article-title":"Restoration of domain folding and interdomain assembly by second\u2010site suppressors of the \u0394F508 mutation in CFTR","volume":"24","author":"L He","year":"2010","journal-title":"FASEB J"},{"issue":"6389","key":"pone.0297560.ref051","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/358761a0","article-title":"Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive","volume":"358","author":"GM Denning","year":"1992","journal-title":"Nature"},{"issue":"7","key":"pone.0297560.ref052","doi-asserted-by":"crossref","DOI":"10.1091\/mbc.E21-11-0578","article-title":"Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants. Miller E, editor","volume":"33","author":"EF McDonald","year":"2022","journal-title":"Mol Biol Cell"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0297560","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T13:35:34Z","timestamp":1706189734000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0297560"}},"subtitle":[],"editor":[{"given":"Jeffrey L","family":"Brodsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,25]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0297560","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.05.561147","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,25]]}}}