Researchers at Geisinger applied a genomic-first strategy analyzing exome sequences from over 218,000 participants, uncovering pathogenic variants in 2.5% of individuals across 490 rare disease genes. Remarkably, many carriers lacked corresponding clinical diagnoses, underscoring gaps in conventional phenotype-driven detection. This scalable framework broadens understanding of rare genetic disorders’ prevalence, penetrance, and variable phenotypic spectrum, highlighting the value and complexity of genomic screening in population health management.