This study estimates the global point prevalence of rare diseases (RDs) using data from the Orphanet database. Orphanet contains information on 6172 unique RDs, with 71.9% classified as genetic and 69.9% exclusively pediatric. The analysis used epidemiological data from the Orphanet Epidemiological file to calculate global point prevalence. Of the 5304 diseases analyzed, 84.5% had a point prevalence of less than 1/1,000,000. However, 77.3–80.7% of the population burden of RDs was attributed to the 4.2% (n=149) diseases in the most common prevalence range (1–5 per 10,000). The study found a conservative, evidence-based estimate of 3.5–5.9% global point prevalence for RDs, equating to 263–446 million people affected worldwide. This estimate is based on data from 67.6% of RDs, using the European definition of 5 per 10,000 and excluding rare cancers, infectious diseases, and poisonings. The study highlights the need for more accurate and comprehensive data collection to refine these estimates. It also emphasizes the importance of a common definition for RDs to facilitate research and policy development. The study found that national definitions of RDs vary widely, but even the lowest prevalence definition (5 per 100,000) encompasses at least 90.5% of RDs in Orphanet. The study concludes that RDs affect at least 3.5–5.9% of the global population, with the majority of cases falling within the lowest prevalence categories. The study also notes that the number of people affected by RDs is likely higher when considering rare cancers, infectious diseases, and poisonings. Future research should focus on improving data collection and codification systems to better estimate the global burden of RDs.This study estimates the global point prevalence of rare diseases (RDs) using data from the Orphanet database. Orphanet contains information on 6172 unique RDs, with 71.9% classified as genetic and 69.9% exclusively pediatric. The analysis used epidemiological data from the Orphanet Epidemiological file to calculate global point prevalence. Of the 5304 diseases analyzed, 84.5% had a point prevalence of less than 1/1,000,000. However, 77.3–80.7% of the population burden of RDs was attributed to the 4.2% (n=149) diseases in the most common prevalence range (1–5 per 10,000). The study found a conservative, evidence-based estimate of 3.5–5.9% global point prevalence for RDs, equating to 263–446 million people affected worldwide. This estimate is based on data from 67.6% of RDs, using the European definition of 5 per 10,000 and excluding rare cancers, infectious diseases, and poisonings. The study highlights the need for more accurate and comprehensive data collection to refine these estimates. It also emphasizes the importance of a common definition for RDs to facilitate research and policy development. The study found that national definitions of RDs vary widely, but even the lowest prevalence definition (5 per 100,000) encompasses at least 90.5% of RDs in Orphanet. The study concludes that RDs affect at least 3.5–5.9% of the global population, with the majority of cases falling within the lowest prevalence categories. The study also notes that the number of people affected by RDs is likely higher when considering rare cancers, infectious diseases, and poisonings. Future research should focus on improving data collection and codification systems to better estimate the global burden of RDs.