Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
Open accessPublished version of a preprint
Abstract
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are “variants of uncertain significance” (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G Fold ) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆G Fold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196 · see citing works
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
<i>MolProbity</i> : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids
Davis, I., Leaver‐Fay, A., Chen, V. B., Block, J. N., Kapral, G. J., Wang, X., Murray, L. W., Arendall, W. B., Snoeyink, J. S., Richardson, J. S., et al. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm216 · Cited by 3,915 · see citing works
CADD: predicting the deleteriousness of variants throughout the human genome
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1016 · Cited by 3,534 · see citing works
Highly accurate protein structure prediction for the human proteome
Tunyasuvunakool, K., Adler, J., Wu, Z., Green, T., Zielinski, M., Žídek, A., Bridgland, A., Cowie, A., Meyer, C., Laydon, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03828-1 · Cited by 3,025 · see citing works
The InterPro protein families and domains database: 20 years on
Blum, M., Chang, H.-Y., Chuguransky, S., Grego, T., Kandasaamy, S., Mitchell, A., Nuka, G., Paysan-Lafosse, T., Qureshi, M., Raj, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa977 · Cited by 2,231 · see citing works
Protein degradation and protection against misfolded or damaged proteins.
Goldberg, A. L. (2003) · Nature · doi:10.1038/nature02263 · Cited by 2,088 · see citing works
Guerois, R., Nielsen, J. E., & Serrano, L. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00442-4 · Cited by 1,728 · see citing works
Current Status of the AMOEBA Polarizable Force Field
Ponder, J. W., Wu, C., Ren, P., Pande, V. S., Chodera, J. D., Schnieders, M. J., Haque, I., Mobley, D. L., Lambrecht, D. S., DiStasio, R. A., et al. (2010) · The Journal of Physical Chemistry B · doi:10.1021/jp910674d · Cited by 1,440 · see citing works
Self-citationIn vivo aspects of protein folding and quality control
Balchin, D., Hayer-Hartl, M. K., & Hartl, F. U. (2016) · Science · doi:10.1126/science.aac4354 · Cited by 1,432 · see citing works
Apweiler, R. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.37 · Cited by 1,079 · see citing works
Improved prediction of protein-protein interactions using AlphaFold2
Bryant, P., Pozzati, G., & Elofsson, A. (2021) · doi:10.1101/2021.09.15.460468 · Cited by 1,025 · see citing works
Zhou, H., & Zhou, Y. (2002) · Protein Science · doi:10.1110/ps.0217002 · Cited by 902 · see citing works
Sensorineural hearing loss in children
Smith, R. J., Bale, J. F., & White, K. R. (2005) · The Lancet · doi:10.1016/s0140-6736(05)71047-3 · Cited by 843 · see citing works
Self-citationCUPSAT: prediction of protein stability upon point mutations
Parthiban, V., Gromiha, M. M., & Schomburg, D. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl190 · Cited by 697 · see citing works
Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins
Shi, Y., Xia, Z., Zhang, J., Best, R. B., Wu, C., Ponder, J. W., & Ren, P. Y. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct4003702 · Cited by 692 · see citing works
Rodrigues, C. H. M., Pires, D. E. V., & Ascher, D. B. (2020) · Protein Science · doi:10.1002/pro.3942 · Cited by 687 · see citing works
A structural biology community assessment of AlphaFold2 applications
Akdel, M., Pires, D. E. V., Pardo, E. P., Jänes, J., Zalevsky, A. O., Mészáros, B., Bryant, P., Good, L. L., Laskowski, R. A., Pozzati, G., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00849-w · Cited by 675 · see citing works
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss
Sloan-Heggen, C., Bierer, A. O., Shearer, A. E., Kolbe, D. L., Nishimura, C. J., Frees, K. L., Ephraim, S. S., Shibata, S. B., Booth, K. T. A., Campbell, C. A., et al. (2016) · Human Genetics · doi:10.1007/s00439-016-1648-8 · Cited by 562 · see citing works
Self-citationComprehensive genetic testing for hereditary hearing loss using massively parallel sequencing
Shearer, A. E., DeLuca, A. P., Hildebrand, M. S., Taylor, K. R., Gurrola, J. G., Scherer, S., Scheetz, T. E., & Smith, R. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012989107 · Cited by 337 · see citing works
Self-citationBenchmarking AlphaFold for protein complex modeling reveals accuracy determinants
Yin, R., Feng, B. Y., Varshney, A., & Pierce, B. G. (2021) · doi:10.1101/2021.10.23.465575 · Cited by 335 · see citing works
Benchmarking <scp>AlphaFold</scp> for protein complex modeling reveals accuracy determinants
Yin, R., Feng, B. Y., Varshney, A., & Pierce, B. G. (2022) · Protein Science · doi:10.1002/pro.4379 · Cited by 335 · see citing works
Molecular Mechanisms of Disease-Causing Missense Mutations
Stefl, S. K., Nishi, H., Petukh, M. G., Panchenko, A. R., & Alexov, E. G. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.07.014 · Cited by 334 · see citing works
On the pH‐optimum of activity and stability of proteins
Talley, K., & Alexov, E. G. (2010) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22786 · Cited by 316 · see citing works
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes
Azaiez, H., Booth, K. T. A., Ephraim, S. S., Crone, B., Black-Ziegelbein, E. A., Marini, R. J., Shearer, A. E., Sloan-Heggen, C., Kolbe, D. L., Casavant, T. L., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.08.006 · Cited by 300 · see citing works
Self-citationAlford, R. L., ARNOS, K. S., Fox, M., Lin, J., Palmer, C. G. S., Pandya, A., Rehm, H. L., Robin, N. H., Scott, D. A., & Yoshinaga‐Itano, C. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.2 · Cited by 269 · see citing works
AF2Complex predicts direct physical interactions in multimeric proteins with deep learning
Gao, M., Nakajima An, D., Parks, J. M., & Skolnick, J. (2022) · Nature Communications · doi:10.1038/s41467-022-29394-2 · Cited by 252 · see citing works
Araya, C. L., Fowler, D. M., Chen, W., Muniez, I., Kelly, J. W., & Fields, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209751109 · Cited by 230 · see citing works
Montanucci, L., Capriotti, E., Frank, Y., Ben-Tal, N., & Fariselli, P. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2923-1 · Cited by 167 · see citing works
Biophysical and Mechanistic Models for Disease-Causing Protein Variants
Stein, A., Fowler, D. M., Hartmann‐Petersen, R., & Lindorff‐Larsen, K. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.01.003 · Cited by 162 · see citing works
Shearer, A. E., Eppsteiner, R. W., Booth, K. T. A., Ephraim, S. S., Gurrola, J. G., Simpson, A. C., Black-Ziegelbein, E. A., Joshi, S., Ravi, H., Giuffre, A. C., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.09.001 · Cited by 151 · see citing works
Self-citationMassively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care
Shearer, A. E., & Smith, R. J. H. (2015) · Otolaryngology–Head and Neck Surgery · doi:10.1177/0194599815591156 · Cited by 144 · see citing works
Self-citationModeling Effects of Human Single Nucleotide Polymorphisms on Protein-Protein Interactions
Teng, S., Madej, T., Panchenko, A. R., & Alexov, E. G. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2008.12.3904 · Cited by 125 · see citing works
Advancing genetic testing for deafness with genomic technology
Shearer, A. E., Black-Ziegelbein, E. A., Hildebrand, M. S., Eppsteiner, R. W., Ravi, H., Joshi, S., Guiffre, A. C., Sloan, C. M., Happe, S., Howard, S., et al. (2013) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2013-101749 · Cited by 124 · see citing works
Self-citationLiming, B. J., Carter, J., Cheng, A. T. L., Choo, D. I., Curotta, J., Carvalho, D., Germiller, J. A., Hone, S., Kenna, M. A., Loundon, N., et al. (2016) · International Journal of Pediatric Otorhinolaryngology · doi:10.1016/j.ijporl.2016.09.016 · Cited by 114 · see citing works
Self-citationWitham, S., Takano, K., Schwartz, C. E., & Alexov, E. G. (2011) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.23065 · Cited by 99 · see citing works
Takano, K., Liu, D., Tarpey, P. S., Gallant, E. M., Lam, A., Witham, S., Alexov, E. G., Chaubey, A., Stevenson, R. E., Schwartz, C. E., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds292 · Cited by 94 · see citing works
Computational analysis of missense mutations causing Snyder-Robinson syndrome
Zhang, Z., Teng, S., Wang, L., Schwartz, C. E., & Alexov, E. G. (2010) · Human Mutation · doi:10.1002/humu.21310 · Cited by 90 · see citing works
Li, M. M., Tayoun, A. N. A., DiStefano, M. T., Pandya, A., Rehm, H. L., Robin, N. H., Schaefer, A. M., & Yoshinaga‐Itano, C. (2022) · Genetics in Medicine · doi:10.1016/j.gim.2022.03.018 · Cited by 75 · see citing works
Self-citationScreening of mutations affecting protein stability and dynamics of FGFR1—A simulation analysis
Doss, C. G. P., Rajith, B., Garwasis, N., Mathew, P. R., Raju, A. S., Apoorva, K. A., William, D. H., Sadhana, N. R., Tanwar, H., & Dike, I. P. (2012) · Applied & Translational Genomics · doi:10.1016/j.atg.2012.06.002 · Cited by 72 · see citing works
DDGun: an untrained predictor of protein stability changes upon amino acid variants
Montanucci, L., Capriotti, E., Birolo, G., Benevenuta, S., Pancotti, C., Lal, D., & Fariselli, P. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac325 · Cited by 71 · see citing works
Boosting Free-Energy Perturbation Calculations with GPU-Accelerated NAMD
Chen, H., Maia, J. D. C., Radak, B. K., Hardy, D. J., Cai, W., Chipot, C. J., & Tajkhorshid, E. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00745 · Cited by 69 · see citing works
A profound computational study to prioritize the disease-causing mutations in PRPS1 gene
Agrahari, A. K., Sneha, P., Doss, C. G. P., Ramamoorthy, S., & Zayed, H. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0121-2 · Cited by 69 · see citing works
Classifying the Binding Modes of Disordered Proteins
Fuxreiter, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228615 · Cited by 64 · see citing works
Hilgert, N., Alasti, F., Dieltjens, N., Pawlik, B., Wollnik, B., Uyguner, Z. O., Delmaghani, S., Weil, D., Petit, C., Danis, E. P., et al. (2008) · Clinical Genetics · doi:10.1111/j.1399-0004.2008.01053.x · Cited by 63 · see citing works
Self-citationImproving the Accuracy of Protein Thermostability Predictions for Single Point Mutations
Duan, J., Lupyan, D., & Wang, L. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.05.020 · Cited by 63 · see citing works
Zhang, Z., Norris, J. W., Schwartz, C. E., & Alexov, E. G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020373 · Cited by 59 · see citing works
Navigating genetic diagnostics in patients with hearing loss
Sloan-Heggen, C., & Smith, R. J. (2016) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000410 · Cited by 40 · see citing works
Self-citationIn silico Mapping of Protein Unfolding Mutations for Inherited Disease
McCafferty, C. L., & Sergeev, Y. V. (2016) · Scientific Reports · doi:10.1038/srep37298 · Cited by 32 · see citing works
Gallant, E., Francey, L. J., Fetting, H., Kaur, M., Hakonarson, H. H., Clark, D. M., Devoto, M., & Krantz, I. D. (2013) · American Journal of Otolaryngology · doi:10.1016/j.amjoto.2012.11.002 · Cited by 31 · see citing works
Bowles, B., Ferrer, A., Nishimura, C. J., Pinto e Vairo, F., Rey, T., Leheup, B., Sullivan, J., Schoch, K., Stong, N., Agolini, E., et al. (2021) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62347 · Cited by 20 · see citing works
Self-citationBuonfiglio, P. I., Bruque, C. D., Lotersztein, V., Luce, L. N., Giliberto, F., Menazzi, S., Francipane, L., Paoli, B., Goldschmidt, E., Elgoyhen, A. B., et al. (2022) · Scientific Reports · doi:10.1038/s41598-021-04081-2 · Cited by 19 · see citing works
Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking
Tollefson, M. R., Litman, J. M., Qi, G., O’Connell, C. E., Wipfler, M. J., Marini, R. J., Bernabe, H. V., Tollefson, W. T. A., Braun, T. A., Casavant, T. L., et al. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.06.030 · Cited by 17 · see citing works
Self-citationStructural biology at the scale of proteomes
Bouatta, N., & AlQuraishi, M. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-00924-w · Cited by 12 · see citing works
Bereshneh, A. H., Rezaei, Z., Jafarinia, E., Rajabi, F., Ashrafi, M. R., Tavasoli, A. R., & Garshasbi, M. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.03.012 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Singh, J., Randle, M. R., Walters, B. J., & Cox, B. C. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1369282 · Cited by 13 · see citing works
Genetic testing for pediatric sensorineural hearing loss in the era of gene therapy
Shearer, A. E. (2024) · Current Opinion in Otolaryngology & Head & Neck Surgery · doi:10.1097/moo.0000000000001005 · Cited by 7 · see citing works
METTL23 Variants and Patients With Normal-Tension Glaucoma
Scheetz, T. E., Tollefson, M. R., Roos, B. R., Boese, E. A., Pouw, A. E., Stone, E. M., Schnieders, M. J., & Fingert, J. H. (2024) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2024.3829 · Cited by 6 · see citing works
Self-citationHuman organoids for rapid validation of gene variants linked to cochlear malformations
Zafeer, M. F., Ramzan, M., Duman, D., Mutlu, A., Seyhan, S., Kalcioglu, M. T., Fítöz, S., DeRosa, B. A., Guo, S., Dykxhoorn, D. M., et al. (2025) · Human Genetics · doi:10.1007/s00439-024-02723-9 · Cited by 6 · see citing works
Tsai, C., Hsu, J. S., Chen, P., & Wu, C. (2024) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2024.2396866 · Cited by 5 · see citing works
Genetic heterogeneity in hereditary hearing loss: Potential role of kinociliary protein TOGARAM2
Ramzan, M., Zafeer, M. F., Abad, C., Guo, S., Owrang, D., Alper, Ö. M., Mutlu, A., Atık, T., Duman, D., Bademci, G., et al. (2024) · European Journal of Human Genetics · doi:10.1038/s41431-024-01562-6 · Cited by 5 · see citing works
Functional Studies of Deafness-Associated Pendrin and Prestin Variants
Takahashi, S., Kojima, T., Wasano, K., & Homma, K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052759 · Cited by 4 · see citing works
Du, W., Huang, J., Zhang, A., Zhao, F., Chen, T., McDermott, Q. M., Zheng, T., Wang, H., Zhang, R., Zhang, X., et al. (2025) · Advanced Science · doi:10.1002/advs.202410063 · Cited by 4 · see citing works
Di, X., He, T., Zhou, Y., Li, X., Feng, J., Su, C., & Bai, P. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1561326 · Cited by 4 · see citing works
Gogal, R. A., Nessler, A. J., Thiel, A. C., Bernabe, H. V., Corrigan, R. A., Cousineau, L. M., Litman, J. M., Miller, J., Qi, G., Speranza, M. J., et al. (2024) · The Journal of Chemical Physics · doi:10.1063/5.0214652 · Cited by 2 · see citing works
Self-citationA rare variant in TRIOBP linked to occupational noise exposure in Meniere disease
Cruz‐Granados, P., Bortoletto, G. B., Zhang, Y., Nadar‐Ponniah, P. T., Bagheri-Loftabad, K., Sartorato, E. L., Sánchez‐Sellero, I., Soto-Varela, A., & Lopez-Escamez, J. A. (2025) · Genes & Diseases · doi:10.1016/j.gendis.2025.101993 · Cited by 2 · see citing works
Rhim, J. W., Kim, D.-K., Han, J. Y., & Park, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e36717 · Cited by 2 · see citing works
Molecular Determinants of TMC Protein Biogenesis and Trafficking
Shao, D., Tan, J., Fan, X., Shu, Y., Qu, Q., & Tang, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136356 · Cited by 1 · see citing works
Harnessing AlphaFold3 to elucidate BBSome structure and protein partners
Guo, D., Rouabhi, Y., Tollefson, M. R., Vorhies, K., & Rahmouni, K. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00804.2025 · Cited by 1 · see citing works
Self-citationGwack, J., Kim, N., & Park, J. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46050300
Liu, X., Li, T., & Sun, J. (2024) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2024.108321
Verma, S., Verma, S., Siddiqi, Z., Raza, S. T., Faruqui, T., Ansari, A. I., Abbas, M., & Mahdi, F. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10417-2
Young, B. P., Nyunt, A. W., Clymer, M. A., Tollefson, M. R., Roos, B. R., Schnieders, M. J., Robin, A. L., & Fingert, J. H. (2025) · Ophthalmology Glaucoma · doi:10.1016/j.ogla.2025.08.003
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Gogal, R. A., Cox, G. M., Kolbe, D. L., Odell, A. D., Ovel, C., McCormick, K., Hong, B., Azaiez, H., Casavant, T. L., Smith, R. J., et al. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1012085
Self-citationChen, L., Yao, M., Tang, H., Zhao, J., Mu, D., Wang, D., Yu, S., Guo, L., Cao, Q., Jiang, L., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.103093
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- Authors
- Tollefson, M. R., Gogal, R. A., Weaver, A. M., Schaefer, A. M., Marini, R. J., Azaiez, H., Kolbe, D. L., Wang, D., Weaver, A. E., Casavant, T. L., Braun, T. A., Smith, R. J. H., & Schnieders, M. J.
- Affiliations
- University of Iowa (US)
- University of Iowa Hospitals and Clinics (US)
- Corresponding author
- Smith, Richard J. H.
- Schnieders, Michael J.
- ORCID
- Venue
- Human Genetics
- Published
- 2023-04-22
- Volume
- 142
- Issue
- 6
- Pages
- 819-834
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC10182131
- OpenAlex
- W4366742193
- Cited by
- 20
- References
- 58
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Human Genetics (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Division of Chemistry (1751688)
- National Science Foundation (000390183)
- National Institute of General Medical Sciences (T32GM008365)
- National Institute on Deafness and Other Communication Disorders (R01DC012049, R01DC002842, R01DC017955)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- variants of uncertain significance, hereditary hearing loss, missense mutations, protein folding stability, folding free energy, AlphaFold2, AMOEBA force field, CADD score, variant reclassification, genetic diagnosis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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