StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritize potentially pathogenic genetic variation
Open accessPublished version of a preprint
Abstract
Summary: Missense mutations that change protein stability are strongly associated with human genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel tool to prioritize variants predicted to cause strong instability in essential proteins. We show that by filtering by ΔΔG values and then prioritizing by StabilitySort Z-scores, we are able to more accurately discriminate pathogenic, protein-destabilizing mutations from population variation, compared with other mutation effect predictors. Availability and implementation: StabilitySort is available as a web service (https://www.stabilitysort.org), as a data download for integration with other tools (https://www.stabilitysort.org/download) or can be deployed as a standalone system from source code (https://gitlab.com/baaron/StabilitySort). Supplementary information: Supplementary data are available at Bioinformatics online.
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Cites
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Highly accurate protein structure prediction for the human proteome
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Predicting the pathogenicity of missense variants using features derived from AlphaFold2
Schmidt, A., Röner, S., Mai, K., Klinkhammer, H., Kircher, M., & Ludwig, K. U. (2023) · Bioinformatics · doi:10.1093/bioinformatics/btad280 · Cited by 79 · see citing works
- Authors
- Chuah, A., Li, S., Do, A., Field, M., & Andrews, D.
- Affiliations
- Australian National University (AU)
- Genome Informatics Laboratory, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University , Canberra, ACT, Australia
- College of Public Health, Medical and Veterinary Science, James Cook University , Cairns, QLD, Australia
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-07-08
- Volume
- 38
- Issue
- 17
- Pages
- 4220-4222
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- OpenAlex
- W4284964246
- Cited by
- 5
- References
- 7
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Bioinformatics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- ResearchOnline - JCU (James Cook University) (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- BioPlatforms Australia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- protein stability, missense mutations, pathogenic variant prediction, AlphaFold2, ΔΔG, essential proteins, mutation effect prediction, web services
- MeSH terms
- Humans, Mutation, Proteins, Software, Genetic Variation, Genome, Protein Stability
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