{"doi":"10.1038/s41586-024-07556-0","title":"A deep catalogue of protein-coding variation in 983,578 individuals","abstract":". Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.","journal":"Nature","year":2024,"id":416670,"datarank":1.864896942247018,"base_score":4.700480365792417,"endowment":4.700480365792417,"self_citation_contribution":0.7050720548688626,"citation_network_contribution":1.1598248873781556,"self_endowment_contribution":0.7050720548688626,"citer_contribution":1.1598248873781556,"corpus_percentile":88.6361878239344,"corpus_rank":1470,"citation_count":109,"citer_count":100,"citers_with_citation_signal":56,"citers_with_endowment":56,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":25.0,"fair_percentile":40.966065423417916,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":327043,"name":"Xiaodong Bai","orcid":"0000-0002-6363-2764","position":1,"is_corresponding":false},{"id":1201215,"name":"Siying Chen","orcid":"0000-0001-5545-9431","position":2,"is_corresponding":false},{"id":843673,"name":"Suying Bao","orcid":"0000-0002-6220-0257","position":3,"is_corresponding":false},{"id":1201903,"name":"Chuanyi Zhang","orcid":null,"position":4,"is_corresponding":false},{"id":27578,"name":"Manav Kapoor","orcid":"0000-0001-6682-940X","position":5,"is_corresponding":false},{"id":348255,"name":"Joshua Backman","orcid":"0000-0001-7262-0880","position":6,"is_corresponding":false},{"id":305310,"name":"Tyler Joseph","orcid":"0000-0001-6013-7285","position":7,"is_corresponding":false},{"id":327046,"name":"Evan K. Maxwell","orcid":"0000-0002-7325-7531","position":8,"is_corresponding":false},{"id":844937,"name":"George Mitra","orcid":null,"position":9,"is_corresponding":false},{"id":1201216,"name":"Alexander Gorovits","orcid":"0000-0002-5067-6557","position":10,"is_corresponding":false},{"id":844932,"name":"Adam J. Mansfield","orcid":null,"position":11,"is_corresponding":false},{"id":843674,"name":"Boris Boutkov","orcid":"0000-0002-9134-0769","position":12,"is_corresponding":false},{"id":1201904,"name":"Sujit Gokhale","orcid":null,"position":13,"is_corresponding":false},{"id":327905,"name":"Lukas Habegger","orcid":null,"position":14,"is_corresponding":false},{"id":61925,"name":"Anthony Marcketta","orcid":"0000-0001-6356-3343","position":15,"is_corresponding":false},{"id":16089,"name":"Adam E. Locke","orcid":"0000-0001-6227-198X","position":16,"is_corresponding":false},{"id":815245,"name":"Liron Ganel","orcid":"0000-0002-8762-622X","position":17,"is_corresponding":false},{"id":1741,"name":"Alicia Hawes","orcid":null,"position":18,"is_corresponding":false},{"id":24981,"name":"Michael D. Kessler","orcid":"0000-0003-1258-5221","position":19,"is_corresponding":false},{"id":472766,"name":"Deepika Sharma","orcid":"0000-0002-5840-8266","position":20,"is_corresponding":false},{"id":327047,"name":"Jeffrey Staples","orcid":"0000-0002-9132-235X","position":21,"is_corresponding":false},{"id":272374,"name":"Jonas Bovijn","orcid":"0000-0001-7436-4446","position":22,"is_corresponding":false},{"id":884557,"name":"Sahar Gelfman","orcid":"0000-0002-4727-7862","position":23,"is_corresponding":false},{"id":1201905,"name":"Alessandro Di Gioia","orcid":null,"position":24,"is_corresponding":false},{"id":556293,"name":"Veera M. Rajagopal","orcid":"0000-0002-5236-168X","position":25,"is_corresponding":false},{"id":327041,"name":"Alexander Lopez","orcid":"0000-0002-4769-5650","position":26,"is_corresponding":false},{"id":1201906,"name":"Jennifer Rico Varela","orcid":null,"position":27,"is_corresponding":false},{"id":620277,"name":"Jesús Alegre-Díaz","orcid":"0000-0001-9390-3871","position":28,"is_corresponding":false},{"id":620275,"name":"Jaime Berúmen","orcid":"0000-0001-6707-3317","position":29,"is_corresponding":false},{"id":620281,"name":"Roberto Tapia-Conyer","orcid":"0000-0003-3814-2904","position":30,"is_corresponding":false},{"id":620276,"name":"Pablo Kuri‐Morales","orcid":"0000-0002-0704-9507","position":31,"is_corresponding":false},{"id":467050,"name":"Jason Torres","orcid":"0000-0002-7537-7035","position":32,"is_corresponding":false},{"id":89767,"name":"Jonathan Emberson","orcid":"0000-0001-7792-9422","position":33,"is_corresponding":false},{"id":6695,"name":"Rory Collins","orcid":"0000-0001-8288-8602","position":34,"is_corresponding":false},{"id":844933,"name":"RGC Management and Leadership Team","orcid":null,"position":35,"is_corresponding":false},{"id":1201907,"name":"Gonçalo Abecasis","orcid":null,"position":36,"is_corresponding":false},{"id":226823,"name":"Giovanni Coppola","orcid":"0000-0003-2105-1061","position":37,"is_corresponding":false},{"id":844934,"name":"Andrew Deubler","orcid":null,"position":38,"is_corresponding":false},{"id":1201908,"name":"Aris Economides","orcid":null,"position":39,"is_corresponding":false},{"id":292065,"name":"Adolfo A. Ferrando","orcid":"0000-0002-6212-8574","position":40,"is_corresponding":false},{"id":240616,"name":"Luca A. Lotta","orcid":"0000-0002-2619-5956","position":41,"is_corresponding":false},{"id":21938,"name":"Alan R. Shuldiner","orcid":"0000-0001-9921-4305","position":42,"is_corresponding":false},{"id":553155,"name":"Katherine Siminovitch","orcid":null,"position":43,"is_corresponding":false},{"id":844935,"name":"Sequencing and Lab Operations","orcid":null,"position":44,"is_corresponding":false},{"id":327891,"name":"Christina Beechert","orcid":null,"position":45,"is_corresponding":false},{"id":1201909,"name":"Erin D. Brian","orcid":null,"position":46,"is_corresponding":false},{"id":1201910,"name":"Laura M. 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For clinical / human-subjects data, deposit in dbGaP or the European Genome-phenome Archive (EGA).","anchors":["yes","partial","no"],"verdict":"partial","current":0.5,"evidence":"Genetic variation data for 821,979 unrelated individuals are made publicly available through the RGC-ME browser (https://rgc-research.regeneron.com/me/home).","why":"The data are stated to be publicly available with no precondition or barrier. [downgraded to 'partial' — no verifiable quote from the paper]","gain":8.33,"priority":"essential","scored":true},{"key":"f_dataset_cited","dimension":"F","label":"Dataset formally cited","action":"Cite the dataset in the reference list like a publication — creator, year, title, repository, DOI/accession — and cite it in-text where it is used. Only a reference- list entry is machine-readable to Crossref/DataCite, and only a citation lets the data earn credit. Cite the clinical / human-subjects repository accession (e.g. from dbGaP or the European Genome-phenome Archive (EGA)) in the reference list.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":"Genetic variation data for 821,979 unrelated individuals are made publicly available through the RGC-ME browser (https://rgc-research.regeneron.com/me/home).","why":"The dataset's identifier (the browser URL) appears only in the body text, not as a reference-list entry. [downgraded to 'no' — no verifiable quote from the paper] [majority verdict 'no' (4/5 passes agreed)]","gain":8.33,"priority":"important","scored":true},{"key":"x_code_availability","dimension":"R","label":"Analysis code available","action":"Publish the analysis code in a public forge, archive a tagged release with a DOI (Zenodo/Software Heritage), and cite that DOI in the paper. NIH DMS Element 2 asks for the tools and code, not only the data — and 'available on request' is not a locator. 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NIH DMS Element 4 asks for both; most papers give neither.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":"Genetic variation data for 821,979 unrelated individuals are made publicly available through the RGC-ME browser (https://rgc-research.regeneron.com/me/home).","why":"The statement indicates availability now but does not specify how long the data will persist. [downgraded to 'no' — no verifiable quote from the paper]","gain":0.0,"priority":"useful","scored":false}],"suggestions":["Mint or cite a persistent identifier for the dataset — a repository DOI or an accession from a registered repository — and print it in the paper. A bare URL is not persistent: it is the single most common cause of a dead data link five years after publication. For clinical / human-subjects data, deposit in dbGaP or the European Genome-phenome Archive (EGA).","Deposit the data in a repository registered in re3data/FAIRsharing (a domain repository such as GEO, SRA, dbGaP, PRIDE, or a generalist such as Zenodo, Dryad, Dataverse) and name it explicitly in the paper. A lab website is not an archive: it has no retention commitment and no accession. For clinical / human-subjects data, deposit in dbGaP or the European Genome-phenome Archive (EGA).","Attach a standard, machine-readable open licence to the deposit — CC0 or CC BY, which is what Horizon Europe and most funders expect — and print the licence identifier in the paper. 'Free to use' is not a licence: it grants nothing a reuser's institution can rely on.","Remove the precondition or justify it. 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Cite the clinical / human-subjects repository accession (e.g. from dbGaP or the European Genome-phenome Archive (EGA)) in the reference list."],"model":"deepseek/deepseek-v4-flash","agent_version":"fair_agent_v8","fulltext_source":"unpaywall_pdf"},"fair_model":"deepseek/deepseek-v4-flash","fair_agent_version":"fair_agent_v8","fair_fulltext_source":"unpaywall_pdf","fair_has_llm":true,"fair_computed_at":"2026-07-20T11:03:17.614133Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}