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Inherited retinal degenerations (IRDs) are the leading cause of blindness in working-age adults and are thought to be monogenic with near-complete penetrance. However, traditional variant discovery based on phenotypic ascertainment may inflate penetrance estimates and obscure the true genotype-phenotype spectrum. We used large biobanks with linked genomic and clinical data to quantify the population-level penetrance of IRD-associated variants. We screened 317,964 All of Us (AoU) participants for loss-of-function or pathogenic IRD variants to curate a cohort with definite IRD-compatible genotypes. We defined three nested International Classification of Diseases (ICD)-9/10 code sets ("IRD," "retinopathy," and "screening") to derive lower- and upper-bound penetrance estimates via disease annotation frequencies (DAFs). Within a cohort of 481 AoU participants with definite IRD-compatible genotypes, DAFs ranged from 9.4% (IRD) to 28.1% (screening), which were enriched relative to the prevalence of the code sets in AoU (p < 0.001). For validation, we examined retinal imaging of UK Biobank (UKB) participants who shared variants with the AoU cohort. In the UKB, 16.1%-27.9% of participants with shared variants exhibited definite or possible IRD features, concordant with AoU estimates. Participant demographics, smoking, socioeconomic status, and comorbidities did not predict penetrance. These results show that the population penetrance of IRD-associated genotypes is markedly lower than traditionally assumed. This suggests that genetic or environmental modifiers are required to manifest disease and that IRD genotypes are more prevalent (0.7%-2.1%) than expected. These findings inform our understanding of the genetic causality of IRDs, impact the clinical use of genetic testing, and have implications for the development of therapies for IRDs.