PT  - JOURNAL ARTICLE
AU  - Aaron Chuah
AU  - Sean Li
AU  - Andrea Do
AU  - Matt A Field
AU  - T. Daniel Andrews
TI  - StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation
AID  - 10.1101/2021.11.28.470298
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.28.470298
4099  - http://biorxiv.org/content/early/2021/12/02/2021.11.28.470298.short
4100  - http://biorxiv.org/content/early/2021/12/02/2021.11.28.470298.full
AB  - Summary Missense mutations that change protein stability are strongly associated with human inherited 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 algorithm to prioritise variants predicted to strongly destabilise essential proteins, available as both a standalone software package and a web-based tool. We demonstrate the utility of this tool by showing that at values of the Stability Sort Z-score above 1.6, pathogenic, protein-destabilising variants from ClinVar are detected at a 58% enrichment, over and above the destabilising (but presumably non-pathogenic) variation already present in the HapMap NA12878 genome.Availability and Implementation StabilitySort is available as both a web service (http://130.56.244.113/StabilitySort/) and can be deployed as a standalone system (https://gitlab.com/baaron/StabilitySort).Contact Dan.Andrews{at}anu.edu.auCompeting Interest StatementThe authors have declared no competing interest.