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Protein domains are highly conserved functional units of proteins. Because they carry functionally significant information, the majority of the coding disease variants are located on domains. Additionally, domains are specific units of the proteins that can be targeted for drug delivery purposes. Here, using information about variants sites associated with diseases, a disease network was built, based on their sharing the same domain and domain variation site. The result was 49,990 disease pairs linked by domain variant site and 533,687 disease pairs that share the same mutated domain. These pairs were compared to disease pairs made using previous methods such as gene identity and gene variant site identity, which revealed that over 8,000 of these pairs were not only missing from the gene pairings but also not found commonly together in literature. The disease network was analyzed from their disease subject categories, which when compared to the gene-based disease network revealed that the domain method results in higher number of connections across disease categories versus within a disease category. Further, a study into the drug repurposing possibilities of the disease network created using domain revealed that 16,902 of the disease pairs had a drug reported for one disease but not the other, highlighting the drug repurposing potential of this new methodology.

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