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One of the most challenging ACMG-AMP guidelines evidence is the PM1, used in about 10% of cases, while the most widely used is the PM2/BS1 reported in 50% of cases. To revisit the PM1 and enrich the BS1 criteria to allow a better classification of human missense variations through protein domains’ information, we built the DOLPHIN system. Using ClinVar data, we showed that DOLPHIN accurately identifies key domain residues without relying on neighboring benign variations, thus revisiting the PM1 evidence. Concomitantly, we demonstrated that DOLPHIN provides a frequency for 32.6% of mutations located in protein domains vs. 7.8% by gnomAD, thus strongly enriching BS1 evidence as illustrated by the 570,498 mutations having a DOLPHIN frequency >1% and not reported in gnomAD. These elements allow an easier classification of amino acid substitutions localized in protein domains that account for almost 40.2% of proteins and where most pathogenic mutations are located.