Homologous Missense Constraint

Input a variant or a gene name bellow or click here to upload a list or a vcf file.


Homologous Missense Constraint measures genetic intolerance information to help inform the clinical significance of missense variants associated with human diseases.

Shown below are (missense) variants annotated with Homologous Missense Constraint score



Homologous Missense Constraint (HMC) is a novel amino acid level measure of genetic intolerance within human populations. We demonstrate that HMC is a novel and powerful tool to predict variant pathogenicity and for disease gene discovery: it is highly precise to predict deleterious missense variants, comparable with state-of-the art supervised meta-predictors; it is orthogonal to many existing variant prioritisation measures, and complementary to existing gene-level or sub-genic measures of genetic constraint.

When one variant could be mapped to more than one Pfam domains, we report the worst HMC score.

Download HMC scores



Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery. medRxiv

Applying in Cardiomyopathies?

We are making this data available ahead of publication. We have ongoing work further evaluating HMC method with specific application to cardiomyopathies. If you are considering a study that uses this tool in that context we ask you to contact us first, so that our decision to preprint does not undermine ongoing work.


The data provided here is available under the ODC Open Database License (ODbL) : you are free to share and modify the data provided here as long as you attribute any public use of the database, or works produced from the database; keep the resulting data-sets open; and offer your shared or adapted version of the dataset under the same ODbL license.

The app is released under a GNU Lesser General Public License v2.1.