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Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population., Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact., Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = -232 pmol/L, β SD  = -0.695, P = 4.43 × 10 -4 ) and higher 30-min glucose (β = 1.20 mmol/L, β SD  = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10 -6 ) and HbA1c (β = 0.113 HbA1c%, β SD  = 0.205, P = 7.84 × 10 -3 ). The variant explained 2.5% of diabetes variance in Greenland., Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations., Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation., Competing Interests: AT has received funding from the 10.13039/501100009708Novo Nordisk Foundation NNF17OC0028328. AA and ZL have received funding from the 10.13039/501100009708Novo Nordisk Foundation (NNF20OC0061343). NG has received funding from the 10.13039/501100009708Novo Nordisk Foundation (NNF16OC0019986). IM has received funding from a Villum Young Investigator grant (19114). MEJ has received research grants from 10.13039/100004325AstraZeneca, 10.13039/100019944Sanofi Aventis, 10.13039/100002429AMGEN, 10.13039/100001003Boehringer Ingelheim and Novo Nordisk A/S. FFS has received funding from the 10.13039/501100001734University of Copenhagen. The population surveys of Greenland were funded by the Department of Health, Greenland, The 10.13039/501100009708Novo Nordisk Foundation (NNF17OC0028136 & NNF17SH0027192), The 10.13039/501100004836Independent Research Fund Denmark, and 10.13039/501100004046Karen Elise Jensen's Foundation. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the 10.13039/501100009708Novo Nordisk Foundation (NNF18CC0034900). None of the funding agencies had any role in study design or collection, analysis, or interpretation of data. The authors have no further conflicts of interest to declare., (© 2022 The Author(s).)