Table 3.

Variant prioritization considerations

ConsiderationResource examples
How common is the variant in a general population? gnomAD 
Has the variant been described as pathogenic? ClinVar, CBioPortal, and COSMIC 
Is there in silico evidence that the variant is pathogenic? MutPhred2, SIFT, MutationTaster, AlphaMissense, Polyphen2, SpiceAI, CADD 
What are known genetic mechanisms of disease in the gene? OMIM, IUIS (for GEI) 
ConsiderationResource examples
How common is the variant in a general population? gnomAD 
Has the variant been described as pathogenic? ClinVar, CBioPortal, and COSMIC 
Is there in silico evidence that the variant is pathogenic? MutPhred2, SIFT, MutationTaster, AlphaMissense, Polyphen2, SpiceAI, CADD 
What are known genetic mechanisms of disease in the gene? OMIM, IUIS (for GEI) 

References: Adzhubei et al., 2013; Broad Institute, 2025; Cerami et al., 2012; Cheng et al., 2023; Poli et al., 2025; Jaganathan et al., 2019; Landrum et al., 2014; McKusick-Nathans Institute of Genetic Medicine, 2025; Ng and Henikoff, 2001; Pejaver et al., 2020; Rentzsch et al., 2019; Steinhaus et al., 2021; Tate et al., 2019.

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