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Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT₂) increase type 2 diabetes (T2D) risk^,. Although the strongest association signal was highly significant (P < 1 × 10⁻²⁰), its contribution to T2D risk was modest (odds ratio (OR) of ∼1.10–1.15)^,,. We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78–6.18; P = 1.64 × 10⁻⁴). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function …