GLP2R

Chr 17

glucagon like peptide 2 receptor

NCBI Gene: 9340 ENSG00000065325 UniProt: O95838 OMIM: 603659

This gene encodes a G protein-coupled receptor that binds glucagon-like peptide 2 and activates adenylyl cyclase to stimulate intestinal growth, enhance nutrient absorption, and maintain gut barrier integrity. Mutations cause autosomal recessive short bowel syndrome, a severe gastrointestinal disorder affecting intestinal function and growth. The gene shows minimal constraint to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a G protein-coupled receptor closely related to the glucagon receptor that binds glucagon-like peptide 2 (GLP-2). Activation of this gene stimulates intestinal growth by increasing villus height, enhancing crypt cell proliferation, and reducing enterocyte apoptosis, thereby promoting nutrient absorption and maintaining gut barrier integrity. Glucagon like protein 2 receptor signaling also regulates intestinal blood flow, supports mucosal healing after injury, and modulates gut hormone secretion. In addition, it has been implicated in metabolic homeostasis and may influence energy balance and glucose metabolism. Dysregulation of this receptor or its signaling pathways is associated with intestinal disorders, including short bowel syndrome and inflammatory bowel disease. This receptor is a potential therapeutic target for enhancing intestinal regeneration and treating gastrointestinal diseases. [provided by RefSeq, Mar 2026]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.93

Clinical Summary— GLP2R

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

78 VUS of 97 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.88

OE 0.65 (0.47–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.16Z-score

OE missense 0.81 (0.73–0.90)

251 obs / 308.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.47–0.93)

0≤0.351.4

Missense OE?0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 22 / 33.8Missense obs/exp: 251 / 308.3Syn Z: -0.52

This gene — mechanism propensity

0.83top 10%

GOF

0.82top 10%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

97 submitted variants in ClinVar

ClinVar

Classification Summary

VUS78

Likely Benign6

Benign8

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	78	0	78
Likely Benign	5	1	6
Benign	6	2	8
Total	89	3	92

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap GLP2R — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →