ArticleGenes2026
Missense Constraint in Intrinsically Disordered Proteins Enhances Missense Variant Interpretation in Neurodevelopmental Disorders.
Article in Genes, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors.
Funding
Abstract
BACKGROUND/
objectivesInterpreting missense variants in intrinsically disordered proteins (IDPs) remains a major challenge, as these proteins lack stable structure and are under-represented in experimental and clinical annotations. Variants occurring in IDPs are disproportionately classified as variants of uncertain significance (VUS), reflecting the absence of appropriate predictive tools rather than true biological neutrality. Here, we address this challenge using a curated dataset of neurodevelopmental disorder (NDD)-associated proteins.
methodsWe integrated curated and predicted disorder annotations from DisProt and MobiDB to characterize the structural landscape of 339 NDD-associated proteins. To quantify a regional genetic constraint, we recalculated the Missense Tolerance Ratio (MTR) using a published framework adapted to the recent gnomAD release (v4.1.0). Integration with 33,124 ClinVar-reported missense variants revealed that, while mean constraint levels differ only modestly across structural states, ordered and structural transition regions show the strongest depletion of missense variation.
resultsMTR identifies localized low-tolerance subregions within IDRs, indicating that these regions are not uniformly permissive and can harbor functionally essential elements.
conclusionsOverall, our results demonstrate that missense constraint in NDD proteins is highly localized and context-dependent, and that integrating high-quality disorder annotations with updated MTR profiles can improve the prioritization and interpretation of missense variants in IDRs and IDPs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.