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Purpose Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well‐studied genes, the direct effects of pathogenic variants are well documented as loss‐of‐function, gain‐of‐function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss‐ or gain‐of‐function would directly inform drug development strategies. Methods We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss‐of‐function. Results We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss‐ or gain‐of‐function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain‐of‐function or hypermorphic pathogenic variants. Conclusions We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.

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