ArticleNature2020
The mutational constraint spectrum quantified from variation in 141,456 humans.
Erratum issuedOpen access · hybridFull text read
In one paragraph
Article in Nature, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6,316 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
6,316citing papers in PubMed, 1 pooled it
1187.9field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
6,316 citing papers in PubMed, 1 synthesis or guideline pooled it, 9,856 citations in OpenAlex.
- Contribution of copy number variants to schizophrenia in East Asian populations.Nature genetics · 2026Pooled it
- Trial
- Quantitative analysis of trafficking defects induced by heterozygous expression of hERG voltage sensor domain variants.Channels (Austin, Tex.) · 2026Article
- EMMVEP: An Ensemble Method for Protein Missense Variant Effect Prediction Based on Multi-Source Feature Fusion.Interdisciplinary sciences, computational life sciences · 2026Article
- Linkage between HLA-B8 and HLA-DQ2.5 contributes to ancestry-dependent risk for celiac disease.Journal of human immunity · 2026Article
- Chromosomal and genetic causes of primary ovarian insufficiency in the Utah population.Journal of the Endocrine Society · 2026Article
- Copy number variant scores are associated with cerebrovascular pathology in aging.Molecular psychiatry · 2026Article
- Genome-Wide Association Study of Pterygium Versus Pinguecula Identifies Loci Associated with Lesion-Type Divergence.Ophthalmology science · 2026Article
- Genetic Architecture of Pediatric Cardiomyopathies Assessed by Whole-Exome Sequencing: Insights Into Early-Onset and Syndromic Forms.Clinical genetics · 2026Article
- Conserved SINE and lineage-variable LINE-1 depletion at neurodevelopmental disorder promoters.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Discovery of novel alleles in Kartagener's syndrome.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- The average individual genome: a survey of nearly 1 million whole-genome sequences.Genome medicine · 2026Article
- Precision oncology in advanced melanoma: molecular landscapes and personalized therapy recommendations from the Molecular Tumor Board Freiburg.NPJ precision oncology · 2026Article
- The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality.Nature genetics · 2026Article
- Small variant calling in the era of long-read sequencing.Nature reviews. Genetics · 2026Review
- MultimodalCirculation · 2026Article
- From genotype to phenotype: reverse phenotyping of a novel INSR variant in a large family with hyperinsulinemic hypoglycemia.Journal of applied genetics · 2026Article
- Microglial GRB2 is essential for brain ventriculogenesis and cerebrospinal fluid homeostasis.The Journal of clinical investigation · 2026Article
- Article
- Expanding Clinical and Variant Spectrum of CBX1-Related Syndrome: Report of Three Novel Cases.Clinical genetics · 2026Article
6,256 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
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- Erratum issued
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Authors and funding
66 authors at 20 institutions in 18 countries.
Konrad J KarczewskiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. konradk@broadinstitute.org.ORCID http://orcid.org/0000-0003-2878-4671
Laurent C FrancioliProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-3039-8895
Grace TiaoProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Beryl B CummingsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jessica AlföldiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-9713-6200
Qingbo WangProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-9110-5830
Ryan L CollinsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1268-9995
Kristen M LaricchiaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Andrea GannaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Daniel P BirnbaumProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Laura D GauthierData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Harrison BrandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Matthew SolomonsonProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nicholas A WattsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Daniel RhodesCentre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, UK.
Moriel Singer-BerkProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eleina M EnglandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eleanor G SeabyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jack A KosmickiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Raymond K WaltersProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8422-6530
Katherine TashmanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Yossi FarjounData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-7002-2868
Eric BanksData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Timothy PoterbaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Arcturus WangProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cotton SeedProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nicola WhiffinProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jessica X ChongDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Kaitlin E SamochaWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.ORCID http://orcid.org/0000-0002-1704-3352
Emma Pierce-HoffmanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Zachary ZappalaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Anne H O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6418-9592
Eric Vallabh MinikelProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ben WeisburdData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Monkol LekDepartment of Genetics, Yale School of Medicine, New Haven, CT, USA.
James S WareProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-6110-5880
Christopher VittalAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Irina M ArmeanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1043-4756
Louis BergelsonData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristian CibulskisData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristen M ConnollyBroad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Miguel CovarrubiasData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stacey DonnellyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Steven FerrieraBroad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stacey GabrielBroad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jeff GentryData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Thibault JeandetData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Diane KaplanData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Christopher LlanwarneData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ruchi MunshiData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sam NovodData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nikelle PetrilloData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
David RoazenData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Valentin Ruano-RubioData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Andrea SaltzmanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Molly SchleicherProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jose SotoData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kathleen TibbettsData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Charlotte TolonenData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Gordon WadeData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Michael E TalkowskiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-2889-0992
Genome Aggregation Database Consortium
Benjamin M NealeProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1513-6077
Mark J DalyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Daniel G MacArthurProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.ORCID http://orcid.org/0000-0002-5771-2290
Broad Institute · USLund University · SECardiff University · GBFinnish Institute for Health and Welfare · FIHelsinki University Hospital · FIUniversity of Eastern Finland · FIUniversity of Helsinki · FIBoston University · USBrigham and Women's Hospital · USChinese University of Hong Kong · HKCleveland Clinic Lerner College of Medicine · USHarvard University · USIcahn School of Medicine at Mount Sinai · USImperial College Healthcare NHS Trust · GBInstituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán · MXJackson Memorial Hospital · USKorea National Institute of Health · KRNational University of Singapore · SGSorbonne Université · FRTampere University · FI
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MGenomic Psychiatry CohortR01MH085548 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI PATO, CARLOS N, PATO, MICHELE T · 2008 to 2012
$16.3MTraining Program in Bioinformatics and Integrative GenomicsT32HG002295 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Peter J Park · 2001 to 2026
$15.8MUW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MComputational resources for genomic interpretation of type 2 diabetesU54DK105566 · NIDDK · BROAD INSTITUTE, INC. · PI MACARTHUR, DANIEL G, NEALE, BENJAMIN MICHAEL · 2014 to 2017
$8.6MClinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2MScalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MScalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumRF1MH115957 · NIMH · BROAD INSTITUTE, INC. · PI MICHAEL E TALKOWSKI · 2026 to 2026
$1.5MAnnotation and interpretation of loss-of-function polymorphisms in human genomesR01GM104371 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI MACARTHUR, DANIEL G · 2013 to 2016
$1.3MScalable tools and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR56MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2018 to 2018
$870kBritish Heart Foundation CS/14/2/30841British Heart Foundation RG/18/10/33842Medical Research Council MC_UP_1102/20NCATS NIH HHS UL1 TR001863NHGRI NIH HHS T32 HG002295NHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006493NHGRI NIH HHS UM1 HG008900NICHD NIH HHS HD081256NICHD NIH HHS R01 HD081256NIDDK NIH HHS U54 DK105566NIGMS NIH HHS F32 GM115208NIGMS NIH HHS R01 GM104371NIMH NIH HHS MH115957NIMH NIH HHS R01 MH085548NIMH NIH HHS R01 MH115957NIMH NIH HHS R56 MH115957NIMH NIH HHS RF1 MH115957
Abstract
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes
Indexed as
AdultBrainCardiovascular DiseasesCohort StudiesDatabases, GeneticExomeExome SequencingFemaleGenes, EssentialGenetic Predisposition to DiseaseGenetic VariationGenome, HumanGenome-Wide Association StudyHumansLoss of Function MutationMalePCSK9 protein, humanProprotein Convertase 9RNA, Messenger
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.