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Background: The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants within genes comprising this pathway, including POMC, PCSK1, LEPR, SH2B1, and NCOA1 (also known as SRC1), have a well-established association with severe obesity. However, the frequency of variants in these genes has not been assessed systematically in a clinically relevant US population. Methods: We sequenced POMC, PCSK1, LEPR, SH2B1, and NCOA1 exons and intron-exon boundaries in 45,866 US individuals with severe obesity (<18 years old, >97th percentile BMI for age; >18 years old, BMI >40kg/m2). This cohort is comprised of individuals sequenced across multiple initiatives, including the Uncovering Rare Obesity® diagnostic genetic testing program. In the current analysis, we included rare variants classified as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS) according to ACMG criteria. Results: 8.2% of individuals with severe obesity carried >1 rare variants in >1 of the 5 studied genes, including 0.3% who carried a P/LP variant and 7.9% who carried a VUS variant. Within the context of a community-focused clinical diagnostic tool, Uncovering Rare Obesity® results demonstrated a higher frequency of P/LP of 0.6% and a 10.0% frequency of VUS genotypes. Conclusions: Overall, in our large US-based cohort of individuals with severe, early-onset obesity, ~8% of individuals carry >1 potentially clinically relevant rare variants in the 5 MC4R pathway genes POMC, PCSK1, LEPR, SH2B1, and NCOA1. Understanding the role of these variants in the pathophysiology of obesity may improve the clinical care of individuals living with these rare genetic diseases of obesity.