ABSTRACT The pandemic caused by the SARS-CoV-2 virus continues to impact public health and the health of individuals, families, and communities. Those with a rare disease may be disproportionately affected because they may have a high risk of exposure to SARS-CoV-2 from their caregivers, housing situations, and need to attend in- person medical appointments. They may also be particularly vulnerable to complications from infection due to their underlying disease condition, immunosuppressive therapies, genetic susceptibility, and/or other factors. The scope of infection among those with rare diseases is unknown. The present proposal will investigate the sero-prevalence of immunity against SARS-CoV-2 among asymptomatic individuals with rare diseases. Specifically, this study will determine the prevalence of detectable antibodies to SARS-CoV-2 (Aim 1) and investigate the immune attributes associated with health outcomes across the life course (Aim 2) among asymptomatic individuals across the United States with one of >280 rare diseases. The anticipated results will provide crucial insights into the magnitude of the COVID-19 pandemic in the context of rare disease and will contribute to the identification of potential targets for a vaccine.