ArticleMolecular biology and evolution2021
Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance.
Article in Molecular biology and evolution, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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
73 citing papers in PubMed, 128 citations in OpenAlex.
- Enhancing Enzyme Activity With Mutation Combinations Guided by Few-Shot Learning and Causal Inference.Angewandte Chemie (International ed. in English) · 2026Article
- Large-scale quaternary structural transitions underlie gain of function of SPOP cancer mutations.Molecular cell · 2026Article
- Pan-cancer proteogenomic interrogation of the ubiquitin-proteasome system.Cell death and differentiation · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- Evidence for G6PD variant classification from multiplexed functional assays.Genome biology · 2026Article
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- Article
- Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System.bioRxiv : the preprint server for biology · 2026Article
- MAVISp: A modular structure-based framework for protein variant effects.Protein science : a publication of the Protein Society · 2026Article
- Continuous Directed Evolution of a Short-Lived Plant Histidinol Dehydrogenase.ACS synthetic biology · 2026Article
- Deconvolving mutation effects on protein stability and function with disentangled protein language models.bioRxiv : the preprint server for biology · 2026Article
- Probing the dark energy in the functional protein universe.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A structure-guided approach to noncoding variant evaluation for transcription factor binding using AlphaFold 3.Nucleic acids research · 2026Article
- Generalizable and scalable protein stability prediction with rewired protein generative models.Nature communications · 2025Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Evidence forbioRxiv : the preprint server for biology · 2025Article
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- Landscapes of missense variant impact for human superoxide dismutase 1.American journal of human genetics · 2025Article
- A method for predicting enzyme substrate specificity residues using homologous sequence information.Protein science : a publication of the Protein Society · 2025Article
13 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Understanding and predicting how amino acid substitutions affect proteins are keys to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analyzed 6,749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyze the structural and mechanistic origins of loss of function and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance. In this way, our results link thermodynamic stability and evolutionary conservation to experimental studies of different properties of protein fitness landscapes.
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.