This study estimates the global point prevalence of rare diseases (RDs) using data from the Orphanet database. Orphanet, a comprehensive resource for RDs, contains information on 6172 unique rare diseases, with 71.9% being genetic and 69.9% exclusively pediatric onset. The global point prevalence was calculated using data from predefined geographic regions. Of the 5304 diseases with defined point prevalence, 84.5% have a prevalence of <1/1,000,000, but 77.3–80.7% of the population burden is attributed to the 4.2% (n=149) diseases in the most common prevalence range (1–5 per 10,000). The analysis yields a conservative estimate of the global population prevalence of RDs at 3.5–5.9%, corresponding to 263–446 million people affected at any given time. This estimate is derived from data from 67.6% of the prevalent rare diseases, using the European definition of 5 per 10,000, and excluding rare cancers, infectious diseases, and poisonings. Future research and the implementation of rare disease codification in healthcare systems will further refine these estimates.This study estimates the global point prevalence of rare diseases (RDs) using data from the Orphanet database. Orphanet, a comprehensive resource for RDs, contains information on 6172 unique rare diseases, with 71.9% being genetic and 69.9% exclusively pediatric onset. The global point prevalence was calculated using data from predefined geographic regions. Of the 5304 diseases with defined point prevalence, 84.5% have a prevalence of <1/1,000,000, but 77.3–80.7% of the population burden is attributed to the 4.2% (n=149) diseases in the most common prevalence range (1–5 per 10,000). The analysis yields a conservative estimate of the global population prevalence of RDs at 3.5–5.9%, corresponding to 263–446 million people affected at any given time. This estimate is derived from data from 67.6% of the prevalent rare diseases, using the European definition of 5 per 10,000, and excluding rare cancers, infectious diseases, and poisonings. Future research and the implementation of rare disease codification in healthcare systems will further refine these estimates.