Predicting Severity of Disease-Causing Variants

Hum Mutat. 2017 Apr;38(4):357-364. doi: 10.1002/humu.23173. Epub 2017 Jan 24.


Most diseases, including those of genetic origin, express a continuum of severity. Clinical interventions for numerous diseases are based on the severity of the phenotype. Predicting severity due to genetic variants could facilitate diagnosis and choice of therapy. Although computational predictions have been used as evidence for classifying the disease relevance of genetic variants, special tools for predicting disease severity in large scale are missing. Here, we manually curated a dataset containing variants leading to severe and less severe phenotypes and studied the abilities of variation impact predictors to distinguish between them. We found that these tools cannot separate the two groups of variants. Then, we developed a novel machine-learning-based method, PON-PS (, for the classification of amino acid substitutions associated with benign, severe, and less severe phenotypes. We tested the method using an independent test dataset and variants in four additional proteins. For distinguishing severe and nonsevere variants, PON-PS showed an accuracy of 61% in the test dataset, which is higher than for existing tolerance prediction methods. PON-PS is the first generic tool developed for this task. The tool can be used together with other evidence for improving diagnosis and prognosis and for prioritization of preventive interventions, clinical monitoring, and molecular tests.

Keywords: genotype-phenotype correlation; mutation severity; phenotype prediction; phenotypic severity; severity prediction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Computational Biology / methods*
  • Disease / classification
  • Disease / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Humans
  • Machine Learning
  • Prognosis
  • Proteins / genetics
  • Reproducibility of Results
  • Severity of Illness Index


  • Proteins