GCK
protein-codingglucokinase
Gene summary
This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]
- MODY2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~55.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0020525
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: ClinGen
Activating variants in the *GCK* gene, which encodes glucokinase, a hexokinase expressed in pancreatic β-cells, were first reported in association with familial hyperinsulinemic hypoglycemia (HH) in 1998 (Glaser et al., PMID: 9435328). These variants typically follow an autosomal dominant inheritance pattern. Gain-of-function variants in *GCK* lead to increased glucokinase activity, resulting in a lowered glucose threshold for insulin secretion. Consequently, pancreatic β-cells inappropriately secrete insulin at low blood glucose concentrations, causing hyperinsulinemic hypoglycemia (PMIDs:37725835,34680961). Heterozygous activating variants are associated with autosomal dominant hyperinsulinism and demonstrate marked phenotypic variability. Clinical presentation ranges from severe neonatal-onset hypoglycemia to milder forms presenting later in childhood or adulthood. While some individuals exhibit persistent hypoglycemia requiring treatment, others may have intermittent or relatively mild symptoms. Rarely, atypical presentations have been reported in individuals with activating variants in *GCK*, including mild or asymptomatic hypoglycemia, variable severity, hypoglycemia unawareness, and diagnosis later in life. Considerable variability can also be observed within families. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern as well as molecular mechanism and phenotypic variability underlying the *GCK*-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes autosomal dominant *GCK*- related hyperinsulinemic hypoglycemia caused by activating (GOF) variants only. Autosomal dominant forms of monogenic hyperglycemia caused by heterozygous inactivating (LOF) variants (MONDO:0015967) and permanent neonatal diabetes caused by bi-allelic inactivating variants are curated separately as semi-dominant *GCK*-related monogenic diabetes. The clinical presentation of individuals with activating variants in *GCK* is characterized by hyperinsulinism, typically presenting as persistent or intermittent hypoglycemia during the neonatal or infantile period, although later-presenting cases have also been reported. Activating variants lower the glucose threshold for insulin secretion by increasing glucokinase activity, resulting in inappropriate insulin release at low blood glucose concentrations. Affected individuals can activate ketogenesis after prolonged fasting, a distinguishing feature from other forms of hyperinsulinism. Many affected individuals have a partial response to medical therapy, particularly diazoxide, although treatment response is variable. These variants predominantly cluster in the allosteric activator site within the small domain near the hinge region, where they stabilize the active conformation of the enzyme and increase glucose affinity. However, additional activating variants have been identified in the hinge and distal large-domain regions, demonstrating that multiple structural domains contribute to glucokinase activation through distinct mechanisms (PMIDs: 14517946, 18450771,19790256,15277402, 29425029). Classification of HI as *GCK*-related HI is established by identification of a pathogenic activating GCK variant. In some cases, pancreatic histology may demonstrate enlarged or hyperplastic islets, which can be seen in other HI etiologies. Dominantly acting gain-of-function variants in *GCK* gene have been curated in at least 17 probands across 11 publications (PMIDs: 3468096, 9435328, 21454522, 15277402, 24890200, 37725835,18450771,19884385,11916951,17976205,31094068,) with clinical presentations consistent with GCK- related hyperinsulinemic hypoglycemia. Additional evidence supporting this gene-disease association is available in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been exhaustively curated. The gene–disease relationship is strongly supported by gain-of-function mechanism, with evidence from functional studies demonstrating increased glucokinase activity, expression data, and animal models. The total points for the experimental evidence are 5, and the combined total points for genetic and experimental evidence together are 17. In summary, *GCK* is definitively associated with autosomal dominant hyperinsulinemic hypoglycemia due to activating variants. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes GCEP on the meeting date June 3, 2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100165
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005148
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007453
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100165
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007453
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0100165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0015967
Submitter: ClinGen
*GCK* was first reported in relation to autosomal dominant (AD) monogenic diabetes in 1992 (Froguel et al., PMID: 1545870). This disease entity is often referred to as maturity-onset diabetes of the young (MODY) 2 (MODY2) and *GCK*-MODY, as well as *GCK*-associated hyperglycemia. *GCK* encodes the glucokinase protein, which acts as a glucose sensor that regulates insulin secretion in response to rising blood glucose levels. *GCK*-related hyperglycemia is characterized by lifelong, stable, mild fasting hyperglycemia that falls in the impaired fasting glucose to low diabetic range (HbA1c: 5.6-7.6% and fasting glucose: 100-144 mg/dL) and generally neither responds to nor requires treatment. Furthermore, individuals exhibit a normal response to a glucose load, and generally have a much lower prevalence of the vascular complications that are often associated with diabetes (PMID: 24430320). We have curated the inheritance pattern for *GCK*-related monogenic diabetes as semidominant because hyperglycemia due to GCK deficiency follows a dosage-dependent pattern. Individuals harboring a heterozygous pathogenic loss of function variant display the mild fasting hyperglycemia phenotype described above, whereas the presence of biallelic pathogenic loss of function variants results in permanent neonatal diabetes mellitus (PNDM). PNDM is a more severe presentation characterized by insulin-requiring hyperglycemia with onset occurring within the first six months of life and is often associated with intrauterine growth restriction and low birth weight. It is often found in families of individuals with PNDM, that upon closer evaluation, the parents of the affected individual are found to have mild fasting hyperglycemia, consistent with *GCK*-related hyperglycemia. As such, a semidominant mode of inheritance was selected for this curation, and evidence from families displaying both autosomal dominant and recessive forms of inheritance were included. The mechanism for both *GCK*-related hyperglycemia and PNDM is loss-of-function. Of note, there are also some reports of individuals harboring biallelic *GCK* variants that are diagnosed with diabetes outside the neonatal period (PMID: 24001579, 25015100, 31197960). Numerous variants in *GCK* have been reported in association with *GCK*-related hyperglycemia and PNDM, including missense, nonsense, frameshift, and splicing. Evidence supporting the association of *GCK* with monogenic diabetes includes case level data, segregation data, and experimental data. The aggregated score for genetic evidence, including case-level and segregation data is 12 points. For the purposes of this summary, 25 variants in GCK in 24 probands from 16 publications have been curated: 11 with AD GCK-related hyperglycemia,10 with AR PNDM, and 3 with AR non-neonatal diabetes (PMIDs: 1570017, 11372010, 14578306, 15644838, 18571549, 21104275, 21518409, 23085272, 24001579, 25015100, 25555642, 25850297, 26587058, 27269892, 27289208, 31197960). Additionally, literature describing *GCK* segregation data within families was evaluated (PMIDs: 1545870, 1570017, 11372010, 14578306, 18571549, 21104275, 21518409, 23085272, 26587058, 27269892). More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached, this literature has not been curated exhaustively. This gene-disease relationship is also supported by experimental evidence (total 6 points), including expression studies, animal models, and in vitro functional assays (PMIDs: 7665557, 1354782, 1557365, 17353190, 23715323, 24309898). In summary, *GCK* is definitively associated with semidominant monogenic diabetes, including AD *GCK*-related hyperglycemia and AR PNDM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the *GCK*-related disease entities. autosomal dominant maturity-onset diabetes of the young (MODY) 2 (MIM:125851) and autosomal recessive permanent neonatal diabetes mellitus (MIM:606176) have been lumped together into the current curation because of the overlapping underlying molecular mechanism (loss-of-function *GCK* variants. Familial hyperinsulinemic hypoglycemia, type 3 (MIM:602485) has been split into a separate curation due to the difference in underlying molecular mechanism (heterozygous activating *GCK* variants) and phenotype. Type 2 diabetes (polygenic; MIM:125853) will not be curated since the contribution of *GCK* in these instances is the result of common variants with a small effect.
Inheritance Pattern: AD
Disease ID:MONDO:0007453
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011236
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007455
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007453
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0100165
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: Individuals with Diabetes mellitus, permanent neonatal have been described with early-onset diabetes mellitus, and recognition may allow prompt early care (eg, with rehydration and insulin), as well as decisions regarding longer-term care (eg, some patients with variants in certain genes may respond to specific medications); In Hyperinsulinemic hypoglycemia, familial, recognition may allow prompt treatment of hypoglycemia; At initial diagnosis, hypoglycemia can be corrected with IV glucose in order to prevent brain damage; Long-term management includes diazoxide, somatostatin analogs, nifedipine, glucagon, recombinant IGF-I, glucocorticoids, human growth hormone, and dietary intervention; If aggressive medical management fails or is not possible (for example, in the case of some individuals with severe AR disease), pancreatic resection may be considered; In MODY, recognition of the underlying cause of MODY may help direct specific management strategies (eg, choice of medications)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GCK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000162.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 5 | 13 | 82 | 2 | 103 |
| missense | 161 | 300 | 292 | 5 | 5 | 763 |
| nonsense | 50 | 16 | 66 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 80 | 66 | 1 | 147 | ||
| splice donor/acceptor (+/-2bp) | 46 | 17 | 3 | 66 | ||
| Total | 338 | 404 | 310 | 88 | 7 | 1147 |
Highest pathogenic variant AF is 0.000045351586
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000153.1 | 10 | MANE Select | |
| Ensembl | ENSP00000384247.3 | 10 | MANE Select | |
| RefSeq | NP_001341729.1 | 11 | Standard | |
| RefSeq | NP_001341730.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gck | Danio rerio | Structure: pancreatic B cell Quality: decreased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- UDP-<i>N</i>-acetyl-D-galactosamine biosynthesis II
- Glycolysis / Gluconeogenesis - Homo sapiens (human)
- Central carbon metabolism in cancer - Homo sapiens (human)
- Type II diabetes mellitus - Homo sapiens (human)
- Starch and sucrose metabolism - Homo sapiens (human)
Biological Process
- cellular glucose homeostasis
- glycolytic process
- regulation of glycolytic process
- NADP metabolic process
- positive regulation of insulin secretion
Molecular Function
- glucokinase activity
- protein binding
- ATP binding
- glucose binding
- fructokinase activity
Cellular Component
- nucleoplasm
- mitochondrion
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000345378
- Coding exons
- 10
- Length
- 53898
- Individuals with no LoFs
- 125635
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125642
- p
- 0.0000279
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.07 | 148 | 297 | 0.499 | 0.0000193 | 3047 |
| Missense (PolyPhen) | 48 | 123.79 | 0.38776 | 1254 | ||
| Synonymous | 0.274 | 126 | 130 | 0.969 | 0.00000998 | 894 |
| Loss of Function | 3.40 | 4 | 20.7 | 0.194 | 9.01e-7 | 240 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. {ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:18322640, ECO:0000269|PubMed:19146401, ECO:0000269|PubMed:25015100, ECO:0000269|PubMed:8325892}.;
- Disease
- DISEASE: Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:12941786, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:19884385, ECO:0000269|PubMed:20375417, ECO:0000269|PubMed:28247534, ECO:0000269|PubMed:9435328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1360036}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:25015100}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.742
Intolerance Scores
- LoFtool
- 0.00723
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 28.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.864
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |