GCK

Chr 7ADAR

glucokinase

Also known as: FGQTL3, GK, GLK, HHF3, HK4, HKIV, HXKP, LGLK

NCBI Gene: 2645ENSG00000106633UniProt: Q12851

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]

Primary Disease Associations & Inheritance

Diabetes mellitus, noninsulin-dependent, late onsetMIM #125853
AD
Diabetes mellitus, permanent neonatal 1MIM #606176
AR
Hyperinsulinemic hypoglycemia, familial, 3MIM #602485
AD
MODY, type IIMIM #125851
AD
399
ClinVar variants
194
Pathogenic / LP
0.63
pLI score
12
Active trials
Clinical Summary— GCK
🧬
Gene-Disease Validity (ClinGen)
monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
194 Pathogenic / Likely Pathogenic· 155 VUS of 399 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.44LOEUF
pLI 0.635
Z-score 3.40
OE 0.19 (0.09–0.44)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.07Z-score
OE missense 0.50 (0.43–0.57)
148 obs / 296.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.09–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.43–0.57)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 4 / 20.7Missense obs/exp: 148 / 296.8Syn Z: 0.27

ClinVar Variant Classifications

399 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic95
Likely Pathogenic99
VUS155
Likely Benign39
Benign2
Conflicting9
95
Pathogenic
99
Likely Pathogenic
155
VUS
39
Likely Benign
2
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
44
28
23
0
95
Likely Pathogenic
16
73
10
0
99
VUS
2
128
20
5
155
Likely Benign
0
0
19
20
39
Benign
0
0
2
0
2
Conflicting
—9
Total622297425399

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GCK · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GLUCOKINASE; GCK
MIM #138079 · *

Diabetes mellitus, noninsulin-dependent, late onset

MIM #125853

Molecular basis of disorder known

Autosomal dominant

Diabetes mellitus, permanent neonatal 1

MIM #606176

Molecular basis of disorder known

Autosomal recessive

Hyperinsulinemic hypoglycemia, familial, 3

MIM #602485

Molecular basis of disorder known

Autosomal dominant

MODY, type II

MIM #125851

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GCK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Monogenic diabetes.
Bonnefond A et al.·Nat Rev Dis Primers
2023Review
Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY).
Tosur M et al.·J Diabetes Investig
2022Review
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.
Snider KE et al.·J Clin Endocrinol Metab
2013
Transcriptome-wide Mendelian randomization during CD4(+) T cell activation reveals immune-related drug targets for cardiometabolic diseases.
Wu X et al.·Nat Commun
2024
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.
Bonnefond A et al.·Nat Metab
2020
Congenital Hyperinsulinism: Diagnosis and Treatment Update.
Demirbilek H et al.·J Clin Res Pediatr Endocrinol
2017Review
Clinical implications of the glucokinase impaired function - GCK MODY today.
Hulín J et al.·Physiol Res
2020Review
Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.
Jurgens SJ et al.·Nat Genet
2022
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.
Mirshahi UL et al.·Am J Hum Genet
2022Cohort
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Kapoor RR et al.·Eur J Endocrinol
2013Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Plasma Cell Myeloma

Comparing Combinations of Drugs to Treat Newly Diagnosed Multiple Myeloma (NDMM) When a Stem Cell Transplant is Not a Medically Suitable Treatment

RECRUITING
NCT05561387Phase PHASE3SWOG Cancer Research NetworkStarted 2023-10-12
BortezomibDaratumumab and Hyaluronidase-fihjDexamethasone
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIIA Lung Non-Small Cell Cancer AJCC v7

Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)

ACTIVE NOT RECRUITING
NCT02595944Phase PHASE3National Cancer Institute (NCI)Started 2016-07-22
Biospecimen CollectionComputed TomographyEchocardiography Test
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
Acinar Cell CarcinomaAdenoid Cystic CarcinomaAdrenal Cortical Carcinoma

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

ACTIVE NOT RECRUITING
NCT02834013Phase PHASE2National Cancer Institute (NCI)Started 2017-01-30
Biospecimen CollectionComputed TomographyEchocardiography Test
Extensive Stage Lung Small Cell Carcinoma

Testing Maintenance Therapy for Small Cell Lung Cancer in Patients With SLFN11 Positive Biomarker

ACTIVE NOT RECRUITING
NCT04334941Phase PHASE2National Cancer Institute (NCI)Started 2020-07-20
AtezolizumabBiopsy ProcedureBiospecimen Collection
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIA Lung Cancer AJCC v8

Genetic Testing in Screening Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

ACTIVE NOT RECRUITING
NCT02194738Phase NANational Cancer Institute (NCI)Started 2014-09-26
Biospecimen CollectionCarboplatinCisplatin
Clinical Stage III Cutaneous Melanoma AJCC v8Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Cutaneous Melanoma

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

ACTIVE NOT RECRUITING
NCT02506153Phase PHASE3National Cancer Institute (NCI)Started 2015-11-10
Biospecimen CollectionComputed TomographyIpilimumab
Hodgkin LymphomaNon-Hodgkin Lymphoma

Evaluating the Impact of Social and Genetic Factors on Outcomes in Adolescent and Young Adult Cancer Survivors

RECRUITING
NCT06002828ECOG-ACRIN Cancer Research GroupStarted 2023-10-13
Biospecimen CollectionQuality-of-Life AssessmentQuestionnaire Administration
Infiltrating Bladder Urothelial CarcinomaStage II Bladder Urothelial CarcinomaStage III Bladder Urothelial Carcinoma

Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations

RECRUITING
NCT03609216Phase PHASE2Alliance for Clinical Trials in OncologyStarted 2018-12-10
Gemcitabine HydrochlorideCisplatinPegfilgrastim
Recurrent Non-Small Cell Lung CarcinomaStage IV Non-Small Cell Lung Cancer

S1403, Afatinib Dimaleate With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage IV or Recurrent, EGFR Mutation Positive Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING
NCT02438722Phase PHASE2, PHASE3SWOG Cancer Research NetworkStarted 2015-05-07
Afatinib DimaleateCetuximabLaboratory Biomarker Analysis
Stage II Breast CancerStage IIIA Breast Cancer

Comparison of Axillary Lymph Node Dissection with Axillary Radiation for Patients with Node-Positive Breast Cancer Treated with Chemotherapy

ACTIVE NOT RECRUITING
NCT01901094Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2014-02-24
Axillary Lymph Node Dissection (ALND)Nodal Radiation TherapyAxillary Radiation Therapy
Prostate Cancer

Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer

ACTIVE NOT RECRUITING
NCT01368588Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-07
radiation therapyWhole-pelvic radiotherapy (WPRT)

External Resources

Links to major genomics databases and tools