AGRP

protein-coding

agouti related neuropeptide, the group of Neuropeptides

Gene summary

This gene encodes an antagonist of the melanocortin-3 and melanocortin-4 receptor. It appears to regulate hypothalamic control of feeding behavior via melanocortin receptor and/or intracellular calcium regulation, and thus plays a role in weight homeostasis. Mutations in this gene have been associated with late on-set obesity. [provided by RefSeq, Dec 2009]

MANE transcript

NM_001138.2

Inheritance

ClinVar variants

U:20B:2

Top phenotype

Respiratory infections, recurrent, and failure to thrive with or without diarrhea

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr16:67,482,571-67,483,547

External References & Databases

Ensembl (ENSG00000159723)

Transcript & Mutation Effects

hg38 • Region Span ~1.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Respiratory infections, recurrent, and failure to thrive with or without diarrheaAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Pulmonary

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Pulmonary

Rationale: The condition can involve recurrent respiratory infections, and awareness may allow preventative and treatment measures may be beneficial; Cardiovascular anomalies have been described, and awareness may early diagnosis and management

Refs: 34952832

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AGRP variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 19

not providedTotal: 2

ObesityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001138.2. 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 clinvar		1 clinvar	2
missense			19 clinvar	1 clinvar		20
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	20	1	1	22

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001138.2	RefSeq	NP_001129.1	3	MANE Select
ENST00000290953.3	Ensembl	ENSP00000290953.3	3	MANE Select
ENST00000968437.1	Ensembl	ENSP00000638496.1	3	Standard
ENST00000968437.2	Ensembl	ENSP00000638496.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
agrp	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

agrp

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adipocytokine signaling pathway - Homo sapiens (human)
Syndecan-3-mediated signaling events

Biological Process

neuropeptide signaling pathway
circadian rhythm
feeding behavior
adult feeding behavior
hormone-mediated signaling pathway

Molecular Function

signaling receptor binding
neuropeptide hormone activity

Cellular Component

extracellular space
Golgi lumen
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290953
Coding exons: 3
Length: 1243
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125740
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.449	70	81.4	0.860	0.00000532	826
Missense (PolyPhen)		27	33.243	0.81219		313
Synonymous	0.526	29	32.8	0.883	0.00000185	287
Loss of Function	0.331	5	5.87	0.852	3.28e-7	64

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00011	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R (By similarity). Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner. {ECO:0000250, ECO:0000269|PubMed:10371151, ECO:0000269|PubMed:11145747, ECO:0000269|PubMed:15927146, ECO:0000269|PubMed:17041250, ECO:0000269|PubMed:9892020}.;
Disease: DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.353

Intolerance Scores

LoFtool: 0.471
RVIS EVS: -0.01
RVIS percentile EVS: 53.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.926

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium