ArticlePLoS computational biology2025
Assessing variant effect predictors and disease mechanisms in intrinsically disordered proteins.
Article in PLoS computational biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- ProteoCast: a web server to predict, validate, and interpret missense variant effects.Journal of molecular biology · 2026Article
- Why variant effect predictors and multiplexed assays agree and disagree.Nature communications · 2026Article
- Variant characterization in the intrinsically disordered human proteome.Nature structural & molecular biology · 2026Article
- Collective Variable-Guided Engineering of the Free-Energy Surface of a Small Peptide.Journal of chemical information and modeling · 2026Article
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- Pathogenic variations illuminate functional constraints in intrinsically disordered proteins.iScience · 2026Article
- Article
- Calibrated Variant Effect Prediction at the Residue Level Using Conditional Score Distributions.bioRxiv : the preprint server for biology · 2025Article
- Classification models distinguish functional and trafficking effects of KCNQ1 variants to enhance variant interpretation.bioRxiv : the preprint server for biology · 2025Article
- Protein language model identifies disordered, conserved motifs implicated in phase separation.eLife · 2025Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
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2 authors.
Funding
Abstract
Intrinsically disordered regions (IDRs) are central to diverse cellular processes but present unique challenges for interpreting genetic variants implicated in human disease. Unlike structured protein domains, IDRs lack stable three-dimensional conformations and are often involved in regulation through transient interactions and post-translational modifications. These features can affect both the distribution of pathogenic variants and the performance of computational tools used to predict their effects. Here, we systematically assessed the distribution of pathogenic vs benign missense variants across disordered, intermediate, and structured protein regions in the human proteome. Pathogenic variants were notably depleted in IDRs yet were associated with distinct molecular mechanisms, particularly dominant gain- and loss-of-function effects. We evaluated 33 variant effect predictors (VEPs), revealing widespread reductions in sensitivity for pathogenic variants in IDRs, despite high AUROC scores driven by accurate benign variant predictions. We also observed substantial discordance among VEP classifications in disordered regions, underscoring the need for region-aware thresholds and disorder-informed prediction strategies. Incorporating features reflective of IDR biology, such as transient interaction motifs and modification sites, may enhance the accuracy and interpretability of future tools.
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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.