Study Identifies Molecular Differences Between Pathogenic, Benign Variants

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Understanding these genetic variants discovered through sequencing efforts is key to further progress in clinical genetics.

A recent study identified features linked with pathogenic and benign variants that reveal the effects of 1330 disease-associated genes at a molecular level.

While recent large-scale sequencing efforts have enabled the detection of millions of missense variants, understanding which ones will actually alter the function of the protein is challenging.

Most missense variants are considered variants of uncertain significance because their effects remain unknown. Some are pathogenic, while others are benign.

The authors, writing in the Proceedings of the National Academy of Sciences, said understanding these genetic variants discovered through sequencing efforts “is one of the major bottlenecks in clinical genetics.” Getting a better sense of the mechanistic differences between benign and pathogenic variants will help to break that bottleneck in order to develop novel therapies for genetic disorders.

"By considering genetic variation in the context of proteins' three-dimensional organization, we present for the first time an atlas of molecular properties of pathogenic mutations that addresses the differences between benign and disease-causing mutations," said Dennis Lal, PhD, Cleveland Clinic's Lerner Research Institute, Genomic Medicine, and the study's lead author, in a statement.


The authors put their findings on web server to enable research.

A protein's function is closely linked to its 3-dimensional structure. The researchers characterized the variants using >14,000 protein structures and identified 3D features associated with pathogenic and benign variants that illustrated the mutations’ effect at the molecular level.

Features that are more frequently mutated in pathogenic variants compared with benign variants (3D mutational hotspots) may be key to explaining the molecular determinants of pathogenicity, they said.

By examining point mutations from all genes on a set of 40 3D protein features, they found that 18 were significantly associated with pathogenic variants and 14 were significantly associated with benign variants. The remaining 8 had no significant link with any variant type.

They also conducted the same amino acid-level analysis individually for 24 protein functional classes to show the characteristics of the positions of the altered amino acids. There was up to 46% divergence of the class-specific features from the general characteristics obtained by the first analysis. They said that was “consistent with the structural diversity of essential regions across different protein classes.”


Iqbal S, Pérez-Palma E,Jespersen JB, et al. Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants. PNAS. Published online October 26, 2020. doi: 10.1073/pnas.2002660117