GLP1R

Chr 6

glucagon like peptide 1 receptor

Also known as: GLP-1, GLP-1-R, GLP-1R

NCBI Gene: 2740ENSG00000112164UniProt: P43220

This gene encodes a 7-transmembrane protein that functions as a receptor for glucagon-like peptide 1 (GLP-1) hormone, which stimulates glucose-induced insulin secretion. This receptor, which functions at the cell surface, becomes internalized in response to GLP-1 and GLP-1 analogs, and it plays an important role in the signaling cascades leading to insulin secretion. It also displays neuroprotective effects in animal models. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type 2 diabetes and stroke. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

54
ClinVar variants
6
Pathogenic / LP
0.29
pLI score
12
Active trials
Clinical Summary— GLP1R
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic· 36 VUS of 54 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 0.293
Z-score 3.90
OE 0.23 (0.13–0.44)
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.
1.68Z-score
OE missense 0.71 (0.63–0.80)
193 obs / 270.7 exp
Tolerant

Mild missense constraint

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.0.23 (0.13–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.63–0.80)
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.1.13
0≤1.21.6
LoF obs/exp: 7 / 30.1Missense obs/exp: 193 / 270.7Syn Z: -1.06

ClinVar Variant Classifications

54 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
VUS36
Likely Benign4
Benign8
6
Pathogenic
36
VUS
4
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
6
0
6
Likely Pathogenic
0
0
0
0
0
VUS
0
33
3
0
36
Likely Benign
0
2
0
2
4
Benign
0
1
0
7
8
Total0369954

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

View in ClinVar →

Protein Context — Lollipop Plot

GLP1R · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Glucagon-like peptide-1 receptor: mechanisms and advances in therapy.
Zheng Z et al.·Signal Transduct Target Ther
2024Review
Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
Lau J et al.·J Med Chem
2015
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1.
Hammoud R et al.·Nat Rev Endocrinol
2023Review
The Definition and Prevalence of Obesity and Metabolic Syndrome: Correlative Clinical Evaluation Based on Phenotypes.
Engin A·Adv Exp Med Biol
2024Review
GLP-1 Receptor Agonists and Kidney Protection.
Greco EV et al.·Medicina (Kaunas)
2019Review
GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications.
Campbell JE et al.·Cell Metab
2023Review
The expanding incretin universe: from basic biology to clinical translation.
Drucker DJ et al.·Diabetologia
2023Review
Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment.
Kopp KO et al.·Pharmacol Res
2022Review
Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease.
Baggio LL et al.·Mol Metab
2021Review
A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.
Véniant MM et al.·Nat Metab
2024Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
In vivo functional profiling and structural characterization of the human GLP1R A316T variant.
El Eid L et al.·Sci Adv
2026Functional
RYGB induces vagal sensory neuropathy characterized by altered Glp1r expression and enhanced exendin-4 responsiveness in male mice.
Merchant W et al.·Am J Physiol Endocrinol Metab
2026
Integrating Pharmacogenomic Insights in GLP-1 Receptor Agonist Therapy: Direct GLP1R and ARRB1 Variants and Indirect CYP2D6 Influences in Personalized Obesity Management.
Jayathilaka NS et al.·Clin Pharmacol Drug Dev
2025
Meta-analysis of GLP1R, GIPR, ADCY3, and CREB1 expression in osteoarthritis identifies CREB1 as a potential biomarker and therapeutic target.
Alizargar J.·J Clin Orthop Trauma
2025
GLP1R and OCT1 variants modulate semaglutide and metformin response in type 2 diabetes.
Tourtourikov I et al.·Pharmacogenet Genomics
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rectal Cancer PatientsObesity &Amp; OverweightLocally Advanced Rectal Cancer (LARC)

Evaluating the Impact of GLP-1 Receptor Agonists With Total Neoadjuvant Therapy in Rectal Cancer

NOT YET RECRUITING
NCT07314528Phase PHASE2St. James's Hospital, IrelandStarted 2026-04
GLP-1 receptor agonistTotal neoadjuvant therapy (TNT)
glp1 AgonistGene ExpressionSkin Laxity

Ellacor® Micro-Coring Technology® in Fitzpatrick Skin Types I-VI, Including Patients Receiving Glucagon-Like Peptide-1 Receptor Agonists

RECRUITING
NCT07224880Cytrellis Biosystems, Inc.Started 2025-10-14
ellacor
Autosomal Dominant Polycystic KidneyObesity

Glucagon-Like Peptide-1 Receptor Agonist in ADPKD

RECRUITING
NCT06582875Phase PHASE2University of Colorado, DenverStarted 2025-03-06
TirzepatidePlacebo
Diabetic NephropathiesKidney DiseasesRenal Insufficiency, Chronic

Transformative Research in Diabetic Nephropathy 2.0

RECRUITING
NCT07444203University of PennsylvaniaStarted 2025-11-12
Sodium-glucose cotransporter 2 inhibitors (SGLT2i)Renin-angiotensin-aldosterone system blockadeGlucagon-like peptide-1 receptor agonists (GLP 1 RA)
Postural Orthostatic Tachycardia Syndrome (POTS)Healthy

POTS-FLOW: Interplay Between Gut Hormones and Autonomic Postprandial Blood Flow Regulation in Patients With POTS

RECRUITING
NCT07019519Phase NAUniversity of CopenhagenStarted 2025-03-15
Saline/PlaceboGIPR antagonistGLP-1R antagonist
PreDiabetes

Pharmacogenetics of the Response to GLP-1 in Mexican-Americans With Prediabetes

RECRUITING
NCT05119179Phase PHASE4The University of Texas Health Science Center, HoustonStarted 2021-11-22
Semaglutide
Type 2 Diabetes MellitusSusceptibility, Genetic

Association of Gene Polymorphism With Susceptibility to T2DM and the Therapeutic Responses to Exenatide in Chinese Patients With T2DM

RECRUITING
NCT06256419Phase NAThe Affiliated Hospital of Xuzhou Medical UniversityStarted 2024-01-01
GLP-1 receptor agonistresponders group and nonresponders group
Overweight and Obesity

Role of Caveolin 1 (CAV-1) Deficiency in Response to Glucagon-like Peptide 1 (GLP-1) Receptor Agonist Treatment

RECRUITING
NCT06069622Brigham and Women's HospitalStarted 2023-11-01
24-hour ambulatory blood pressureLiberal salt diet
Obesity

Effect of Tirzepatide on Brown Adipose Tissue in Obesity

ACTIVE NOT RECRUITING
NCT06893211Phase PHASE2University Medical Centre LjubljanaStarted 2025-03-18
TirzepatidePlacebo
Incretin Effect

The Effect of GIP, GLP-1 and GLP-2 in Individuals With Genetically Altered Receptor Function

RECRUITING
NCT06194955Phase NAUniversity of CopenhagenStarted 2023-01-04
GIP(1-42)GLP-1GLP-2
Chronic Kidney DiseasesMAFLD

Pathogenesis of Chronic Kidney Disease Associated With Metabolic Dysfunction- Associated Fatty Liver Disease (MAFLD) and Treatment Response of Oral Semaglutide.

NOT YET RECRUITING
NCT07391267Phase NAInstitute of Liver and Biliary Sciences, IndiaStarted 2026-02-01
Semaglutide Oral TabletPlaceboStandard medical treatment
NAFLDDiabetesObesity

GLP-1 RA on Liver OMICS in MASLD

NOT YET RECRUITING
NCT06982378Medical College of WisconsinStarted 2026-07
GLP-1 receptor agonist

External Resources

Links to major genomics databases and tools