Monogenic disorders present a compelling target for drug discovery due to their clear, single-gene etiology. Yet, effective therapies remain scarce, largely because diverse mutation types scattered across a protein obstruct targeted drug design. In this study, we leverage MOGEDO, a curated database of monogenic disorders, to test whether different pathogenic genotypes within a single protein converge on a common molecular mechanism. By clustering MOGEDO proteins into eight functional families and analyzing representative proteins carrying both benign and pathogenic mutations, we integrated molecular dynamics, network analysis, and side-chain entropy metrics. Our findings reveal that distinct pathogenic mutations disrupt the structural and dynamic properties of the wild-type and benign protein through common pathways. By demonstrating that diverse disease-causing mutations manifest a unified pathogenic phenotype, this work provides a framework for designing broad-spectrum therapeutics that target common dysfunctional mechanisms rather than individual mutations.

Monogenic disorders present a compelling target for drug discovery due to their clear, single-gene etiology. Yet, effective therapies remain scarce, largely because diverse mutation types scattered across a protein obstruct targeted drug design. In this study, we leverage MOGEDO, a curated database of monogenic disorders, to test whether different pathogenic genotypes within a single protein converge on a common molecular mechanism. By clustering MOGEDO proteins into eight functional families and analyzing representative proteins carrying both benign and pathogenic mutations, we integrated molecular dynamics, network analysis, and side-chain entropy metrics. Our findings reveal that distinct pathogenic mutations disrupt the structural and dynamic properties of the wild-type and benign protein through common pathways. By demonstrating that diverse disease-causing mutations manifest a unified pathogenic phenotype, this work provides a framework for designing broad-spectrum therapeutics that target common putative intervention sites rather than individual mutations.