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Article

Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes

by
Varsha Rajesh
1,
Dora Evelyn Ibarra
1,2,
Jing Yang
1,
Haichen Zhang
3,†,
Amy Barrett
4,
Eleanor G. Kaplan
1,5,
Amit Kumthekar
1,
Fanny Sunden
6,
Han Sun
1,
Ananta Addala
1,
Aaron Misakian
1,‡,
Lisa R. Letourneau-Freiberg
7,
Colleen O. Jodarski
3,
Kristin A. Maloney
3,
Cécile Saint-Martin
8,
Polly M. Fordyce
5,9,10,11,
Toni I. Pollin
3 and
Anna L. Gloyn
1,4,5,12,*
1
Department of Pediatrics, Division of Endocrinology, Stanford School of Medicine, Stanford, CA 94305, USA
2
Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
3
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
4
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
5
Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA
6
Department of Biochemistry, Stanford School of Medicine, Stanford, CA 94305, USA
7
Kovler Diabetes Center, University of Chicago, Chicago, IL 60637, USA
8
Department of Medical Genetics, AP-HP Pitié-Salpêtrière Hospital, Sorbonne University, 75012 Paris, France
9
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
10
Sarafan ChEM-H, Stanford, CA 94305, USA
11
Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
12
Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, CA 94305, USA
 
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*
Author to whom correspondence should be addressed.
†
Current address: BGI Research, Beijing 100083, China.
‡
Current address: Division of Pediatric Endocrinology, School of Medicine, University of Virginia, Charlottesville, VA 22904, USA.
Int. J. Mol. Sci. 2026, 27(1), 156; https://doi.org/10.3390/ijms27010156
Submission received: 18 November 2025 / Revised: 17 December 2025 / Accepted: 17 December 2025 / Published: 23 December 2025
(This article belongs to the Special Issue Functional Studies and Deep Phenotyping in Monogenic Forms of Diabetes, Severe Insulin Resistance and Hypoglycemia)
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Abstract

Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not always lead to a precise diagnosis, as novel variants are often classified as variants of unknown significance. Variant interpretation requires collation of a framework of evidence, including population, computational, and segregation data, and can be assisted by functional analysis. The inclusion of functional data can be challenging, depending on the number of benign and pathogenic variants available for benchmarking assays. Glucokinase is the rate-limiting step for glucose metabolism in the pancreatic beta-cell and governs the threshold for glucose-stimulated insulin release. Loss-of-function alleles in the glucokinase (GCK) gene are a cause of stable fasting hyperglycemia from birth and/or diabetes. In this study, we functionally characterized 25 variants identified during diagnostic testing or in exome sequencing studies. We assessed their kinetic characteristics, stability, and interaction with pharmacological and physiological regulators. We integrated our functional data with existing data from the ClinGen Monogenic Diabetes Variant Curation Expert Review panel using a gene-specific framework to assist variant classification. We show how functional evidence can aid variant classification, thus enabling diagnostic certainty.
Keywords: glucokinase; MODY; monogenic diabetes; VUS; hypoglycemia glucokinase; MODY; monogenic diabetes; VUS; hypoglycemia

Share and Cite

MDPI and ACS Style

Rajesh, V.; Ibarra, D.E.; Yang, J.; Zhang, H.; Barrett, A.; Kaplan, E.G.; Kumthekar, A.; Sunden, F.; Sun, H.; Addala, A.; et al. Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes. Int. J. Mol. Sci. 2026, 27, 156. https://doi.org/10.3390/ijms27010156

AMA Style

Rajesh V, Ibarra DE, Yang J, Zhang H, Barrett A, Kaplan EG, Kumthekar A, Sunden F, Sun H, Addala A, et al. Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes. International Journal of Molecular Sciences. 2026; 27(1):156. https://doi.org/10.3390/ijms27010156

Chicago/Turabian Style

Rajesh, Varsha, Dora Evelyn Ibarra, Jing Yang, Haichen Zhang, Amy Barrett, Eleanor G. Kaplan, Amit Kumthekar, Fanny Sunden, Han Sun, Ananta Addala, and et al. 2026. "Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes" International Journal of Molecular Sciences 27, no. 1: 156. https://doi.org/10.3390/ijms27010156

APA Style

Rajesh, V., Ibarra, D. E., Yang, J., Zhang, H., Barrett, A., Kaplan, E. G., Kumthekar, A., Sunden, F., Sun, H., Addala, A., Misakian, A., Letourneau-Freiberg, L. R., Jodarski, C. O., Maloney, K. A., Saint-Martin, C., Fordyce, P. M., Pollin, T. I., & Gloyn, A. L. (2026). Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes. International Journal of Molecular Sciences, 27(1), 156. https://doi.org/10.3390/ijms27010156

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