GeneBe

GCGR

protein-coding

glucagon receptor, the group of Glucagon receptor family

Gene summary

The protein encoded by this gene is the glucagon receptor, a member of the secretin receptor family of class B G-protein-coupled receptors (GPCRs). This receptor plays a critical role in maintaining blood glucose homeostasis by mediating the effects of glucagon, including stimulation of hepatic glycogenolysis and gluconeogenesis. This gene is expressed primarily in the liver and kidney but also in the heart, adrenal glands, pancreas, spleen, thymus, cerebral cortex, adipose tissue, and gastrointestinal tract. Mutations in this gene can impair glucagon signaling, leading to dysregulation of glucose metabolism and contributing to the development of non-insulin-dependent diabetes mellitus (type 2 diabetes). Such defects may result in altered glucose production, insufficient counter-regulation during fasting, and increased susceptibility to hyperglycemia. Inactivating mutations in this gene cause resistance to glucagon which is associated with Mahvash disease. [provided by RefSeq, Mar 2026]

MANE transcript

NM_000160.5

Inheritance

AR

ClinVar variants

P:6U:96B:54

Top phenotype

Mahvash disease

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr17:81,804,132-81,814,008

External References & Databases

Ensembl (ENSG00000215644)NCBI Gene (2642)OMIM (138033)HGNC:4192GenCCUniProt (P47871)AlphaFoldClinVar (GCGR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~9.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

GCGR-related hyperglucagonemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018582

Submitter: PanelApp Australia

GCGR-related hyperglucagonemiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018582

Submitter: Labcorp Genetics (formerly Invitae)

GCGR-related hyperglucagonemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018582

Submitter: Ambry Genetics

GCGR-related hyperglucagonemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018582

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mahvash diseaseAR

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: The condition can involve alpha-cell hyperplasia with glucagonemia, and can lead to glucagonomas and/or primitive neuroectodermal tumors, and awareness may allow early diagnosis and management of medical manifestations and neoplasms

Refs: 19657311; 29702528; 30032256; 30294546; 32677665Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GCGR variants in ClinVar

5 Conditions Cataloged
not providedTotal: 152
not specifiedTotal: 52
GCGR-related hyperglucagonemiaTotal: 9
GCGR-related disorderTotal: 8
Type 2 diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000160.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
33
clinvar
9
clinvar
 44
missense
1
clinvar
90
clinvar
10
clinvar
2
clinvar
 103
nonsense
1
clinvar
 1
start loss
0
frameshift
2
clinvar
1
clinvar
 3
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
3
clinvar
 5
Total42964311156

Highest pathogenic variant AF is 0.000047814297

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000160.5RefSeqNP_000151.113MANE Select
ENST00000400723.8EnsemblENSP00000383558.313MANE Select
ENST00000570996.5EnsemblENSP00000460976.111Standard
ENST00000570996.6EnsemblENSP00000460976.111Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
gcgrbDanio rerio

Structure: pancreatic A cell

Quality: hyperplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glucagon signaling pathway - Homo sapiens (human)
  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • GPCRs, Class B Secretin-like
  • Signaling by GPCR
  • Signal Transduction

Biological Process

  • generation of precursor metabolites and energy
  • exocytosis
  • cell surface receptor signaling pathway
  • G protein-coupled receptor signaling pathway
  • adenylate cyclase-modulating G protein-coupled receptor signaling pathway

Molecular Function

  • glucagon receptor activity
  • guanyl-nucleotide exchange factor activity
  • G protein-coupled peptide receptor activity
  • peptide hormone binding

Cellular Component

  • endosome
  • plasma membrane
  • integral component of plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000400723
Coding exons
13
Length
9882
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.662203010.7300.00001983058
Missense (PolyPhen)62108.380.572041169
Synonymous0.3141281330.9650.00000940941
Loss of Function2.101324.10.5390.00000108249

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:19657311, ECO:0000269|PubMed:22908259, ECO:0000269|PubMed:23863937, ECO:0000269|PubMed:27111510, ECO:0000269|PubMed:28514451, ECO:0000269|PubMed:7507321, ECO:0000269|PubMed:9287038}.;

Intolerance Scores

RVIS EVS
0.19
RVIS percentile EVS
67.03

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.577

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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