We assessed variant-level and gene-level population penetrance of obesity and associations with adult BMI and recalled childhood adiposity, and tested the statistical interaction between rare variant carriage and a BMI polygenic score.<h4>Results</h4>Considering experimentally characterized LoF variants (excluding MC4R), we identified 22 heterozygous and 2 homozygous variants in 3 autosomal recessive genes (POMC, PCSK1, LEPR), and 3 autosomal dominant genes (SH2B1, SIM1, KSR2) with at least 10 carriers in the UKBB. The gene discussed is SH2B1; the disease is obesity due to melanocortin 4 receptor deficiency.