Can AlphaFold2 predict the impact of missense mutations on structure?
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Studies have reported that AF2 cannot predict how mutations affect protein structure and stability.
“studies have reported an inability of AF2 to predict the effects of mutations on protein structure and stability14,49,50”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [49]
Some reports have indicated that AF2 does not appear to be well suited to predict the structures of mutated proteins.
“However, some reports have indicated that AF2 does not appear to be well suited to predict the structures of mutated proteins54,55.”
From A structural biology community assessment of AlphaFold2 applications (2022) · cites this paper as [55]
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Highly accurate protein structure prediction with AlphaFold
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Targeting p53 pathways: mechanisms, structures, and advances in therapy
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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
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The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins
Agarwal, V., & McShan, A. C. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01638-w · Cited by 155 · see citing works
“In support of this, studies have reported an inability of AF2 to predict the effects of mutations on protein structure and stability 14,49,50 , which may be due to a training bias on stable structures or an inability to extract signal from small mutations through MSAs.”
ResultThe accuracy of protein structures in solution determined by AlphaFold and NMR
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Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation
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“This points to an important limitation in AF ’ s ability to predict binding speci fi cities and is in line with previous reports on AF ’ s inability to predict the effect of mutations (Buel and Walters, 2022).”
Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation
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Predicting the pathogenicity of missense variants using features derived from AlphaFold2
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Challenges in bridging the gap between protein structure prediction and functional interpretation
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OPUS-Mut: Studying the Effect of Protein Mutation through Side-Chain Modeling
Xu, G., Wang, Q., & Ma, J. (2023) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.2c00847 · Cited by 12 · see citing works
Utilizing protein structure graph embeddings to predict the pathogenicity of missense variants
Danner, M., Begemann, M., Elbracht, M., Kurth, I., & Krause, J. (2025) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqaf097 · Cited by 2 · see citing works
- Authors
- Buel, G. R., & Walters, K. J.
- Affiliations
- National Cancer Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Walters, Kylie J.
- Venue
- Nature Structural & Molecular Biology
- Published
- 2022-01
- Volume
- 29
- Issue
- 1
- Pages
- 1-2
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC11218004
- OpenAlex
- W4206002704
- Cited by
- 332
- References
- 3
- Citations by year
- 2026: 50 · 2025: 70 · 2024: 77 · 2023: 88 · 2022: 47
- FWCI
- 23.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (ZIABC011627)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- AlphaFold2, missense mutations, protein structure prediction, protein conformational ensembles, leader peptide
- MeSH terms
- Protein Domains, Algorithms, Models, Molecular, Proteins, Protein Structure, Secondary, Mutation, Missense, Ubiquitin
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