ASIP

Summary

ASIP (agouti signaling protein, HGNC:745) is a protein-coding gene on chromosome 20q11.22, encoding Agouti-signaling protein (P42127). Signaling protein that functions as an antagonist of melanocyte-stimulating-hormone receptor MC1R, thereby playing a role in the regulation of melanogenesis.

In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes.

Source: NCBI Gene 434 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_001672

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:745
Approved symbol	ASIP
Name	agouti signaling protein
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	ASP
Ensembl gene	ENSG00000101440
Ensembl biotype	protein_coding
OMIM	600201
Entrez	434

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000374954, ENST00000568305, ENST00000962459, ENST00000962460

RefSeq mRNA: 2 — MANE Select: NM_001672 NM_001385218, NM_001672

CCDS: CCDS13232

Canonical transcript exons

ENST00000374954 — 4 exons

Exon	Start	End
ENSE00000661381	34262832	34262893
ENSE00001465248	34268991	34269344
ENSE00001465251	34260365	34260534
ENSE00003921932	34241423	34241489

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 92.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1802 / max 45.7009, expressed in 46 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184207	0.1093	19
184203	0.0219	9
184205	0.0171	7
184202	0.0160	2
184204	0.0159	6

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	92.14	gold quality
left ovary	UBERON:0002119	90.32	gold quality
right ovary	UBERON:0002118	88.69	gold quality
heart left ventricle	UBERON:0002084	83.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.91	gold quality
cardiac ventricle	UBERON:0002082	82.09	gold quality
ovary	UBERON:0000992	79.65	gold quality
skin of leg	UBERON:0001511	74.13	gold quality
skin of abdomen	UBERON:0001416	73.25	gold quality
heart	UBERON:0000948	72.13	gold quality
corpus epididymis	UBERON:0004359	71.51	silver quality
tibial nerve	UBERON:0001323	71.30	gold quality
endocervix	UBERON:0000458	70.90	gold quality
left uterine tube	UBERON:0001303	70.62	gold quality
zone of skin	UBERON:0000014	70.34	gold quality
right atrium auricular region	UBERON:0006631	70.10	gold quality
Brodmann (1909) area 10	UBERON:0013541	69.33	gold quality
cardiac atrium	UBERON:0002081	68.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	63.89	gold quality
body of uterus	UBERON:0009853	62.62	gold quality
cauda epididymis	UBERON:0004360	62.46	silver quality
frontal pole	UBERON:0002795	61.35	gold quality
middle frontal gyrus	UBERON:0002702	61.30	gold quality
paraflocculus	UBERON:0005351	60.91	gold quality
granulocyte	CL:0000094	60.89	gold quality
right lobe of liver	UBERON:0001114	60.68	gold quality
sural nerve	UBERON:0015488	60.02	gold quality
monocyte	CL:0000576	59.22	gold quality
pancreatic ductal cell	CL:0002079	59.18	silver quality
mononuclear cell	CL:0000842	59.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2

Literature-anchored findings (GeneRIF, showing 23)

• polymorphism in the agouti signaling protein gene is associated with human pigmentation (PMID:11833005)
• results show that men and women of similar age and BMI present similar agouti signal protein mRNA levels in omental and subcutaneous abdominal adipocytes but a sexual dimorphism exists in the relationship between its expression and BMI (PMID:12055320)
• Results identify five genes that are down-regulated by agouti signalling protein (ASIP), indicating a likely role for ASIP in human melanogenesis. (PMID:12519127)
• Agouti mRNA levels significantly elevated in type 2 diabetes. Insulin did not regulate agouti mRNA. Agouti can regulate adipogenesis.There are functional consequences of elevated agouti levels in human adipose tissue. (PMID:14633851)
• Our study suggests that the ASIP G>A polymorphism exhibits a dominant effect leading to lighter skin color and that variation in the ASIP gene may have been one of several factors contributing to reductions in pigmentation in some populations. (PMID:15726415)
• ASIP polymorphism was not associated with pigmentation, nevi, or melanoma risk (PMID:15998953)
• An important role for exon 17b of ASIP in cancer cells was identified;alternative splicing isoforms ,hASIP-sa, hASIP-sb, had different effects on cell growth and Fas/FasL-mediated apoptosis in BEL-7404 human hepatoma cells. (PMID:16091846)
• A/G polymorphism in the 3’-UTR region of the agouti signaling protein contributes to dark pigmentation. (PMID:16704456)
• Cocaine- and amphetamine-regulated transcript protein is colocalized with this protein and neuropeptide Y in human hypothalamus. (PMID:17525122)
• ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. (PMID:18488027)
• Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair. (PMID:18488028)
• ASIP polymorphism was found not to be associated with skin malignant melanoma or basal cell carcinoma. (PMID:18637131)
• Polymorphism of pigmentation genes (OCA2 and ASIP) in some populations of Russia (PMID:19382693)
• Single nucleotide polymorphisms in ASIP is associated with basal cell carcinoma (PMID:19384953)
• Further analysis of binding and functional data suggests that the ASIP C-terminal loop (a six-amino-acid segment closed by the final disulfide bond) is essential for high-affinity MC1R binding and inverse agonism. (PMID:20831872)
• Findings suggest that ASIP locus is associated with a number of non-melanoma skin cancers. (PMID:21221757)
• By using a population-based material of high-risk melanoma cases, we demonstrate a significant effect of both MC1R red hair color (RHC) variants and an ASIP haplotype, but could not replicate an association with postulated risk SNPs of TYR and TYRP1. (PMID:22447455)
• An increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03-1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. (PMID:22628150)
• Data show that ASIP TG/TG diplotype, which is known to be associated with melanoma risk, was linked to a 5-fold increase in hazard of death from melanoma. (PMID:25382380)
• ASIP gene mutation is involved in the development of facial pigmented lesions. (PMID:25705849)
• Polymorphisms of ASIP were found to be associated with skin, hair, and eye color in a phenotypically diverse Brazilian population. More research is needed to determine its usefulness in forensic science. (PMID:25801600)
• ASIP expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. (PMID:36536132)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	asip1	ENSDARG00000077858
mus_musculus	a	ENSMUSG00000027596
rattus_norvegicus	Asip	ENSRNOG00000017701

Paralogs (1): AGRP (ENSG00000159723)

Protein

Protein identifiers

Agouti-signaling protein — P42127 (reviewed: P42127)

Alternative names: Agouti switch protein

All UniProt accessions (1): P42127

UniProt curated annotations — full annotation on UniProt →

Function. Signaling protein that functions as an antagonist of melanocyte-stimulating-hormone receptor MC1R, thereby playing a role in the regulation of melanogenesis. Binding to MC1R prevents alpha-MSH-induced signaling and inhibits cAMP production, resulting in down-regulation of eumelanogenesis (brown/black pigment) and increased pheomelanin (yellow/red pigment) synthesis. In higher primates, Agouti may affect the quality of hair pigmentation rather than the pattern of pigment deposition. May also play a role in neuroendocrine aspects of melanocortin action.

Subcellular location. Secreted.

Tissue specificity. Widely expressed at low levels. Highly expressed in the skin. Expressed in adipose tissue.

Disease relevance. Obesity and hypopigmentation (OBHP) [MIM:620195] An autosomal dominant disorder characterized by early-onset obesity, overgrowth, hyperinsulinemia, and hypopigmentation of the skin. Some affected individuals experience hyperphagia and exhibit reduced energy expenditure. The gene represented in this entry is involved in disease pathogenesis. A tandem duplication on chromosome 20 encompassing the neighboring genes ASIP and ITCH creates an ITCH-ASIP transcript consisting of the first two non-coding ITCH exons fused to the ASIP coding exons. This results in ASIP ectopic overexpression controlled by the ubiquitously active ITCH promoter. Ectopically expressed ASIP may antagonize MC4R signaling in the hypothalamus and may affect processes related to eating behavior and energy expenditure.

Domain organisation. The presence of a ‘disulfide through disulfide knot’ structurally defines this protein as a knottin.

Polymorphism. Genetic variants in ASIP define the skin/hair/eye pigmentation variation locus 9 (SHEP9) [MIM:611742]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.

RefSeq proteins (2): NP_001372147, NP_001663* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007733	Agouti	Family
IPR027300	Agouti_dom	Domain
IPR036836	Agouti_dom_sf	Homologous_superfamily

Pfam: PF05039

UniProt features (17 total): disulfide bond 5, strand 4, sequence variant 2, signal peptide 1, chain 1, domain 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1Y7J	SOLUTION NMR
1Y7K	SOLUTION NMR
2KZA	SOLUTION NMR
2L1J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42127-F1	66.03	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (5): 116–123, 93–108, 100–114, 107–125, 111–132

Glycosylation sites (1): 39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 90 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_92, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_VESICLE_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CELLULAR_PIGMENTATION, GOBP_CELL_CELL_SIGNALING, GOBP_PIGMENTATION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, MODULE_379, GOBP_PIGMENT_METABOLIC_PROCESS, GOBP_PIGMENT_GRANULE_ORGANIZATION

GO Biological Process (14): generation of precursor metabolites and energy (GO:0006091), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), adult feeding behavior (GO:0008343), hormone-mediated signaling pathway (GO:0009755), melanosome transport (GO:0032402), melanosome organization (GO:0032438), melanin biosynthetic process (GO:0042438), epigenetic programming in the zygotic pronuclei (GO:0044725), negative regulation of melanin biosynthetic process (GO:0048022), positive regulation of melanin biosynthetic process (GO:0048023), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), epigenetic regulation of gene expression (GO:0040029), pigmentation (GO:0043473)

GO Molecular Function (7): signaling receptor binding (GO:0005102), neuropeptide hormone activity (GO:0005184), melanocortin receptor binding (GO:0031779), type 3 melanocortin receptor binding (GO:0031781), type 4 melanocortin receptor binding (GO:0031782), receptor antagonist activity (GO:0048019), type 1 melanocortin receptor binding (GO:0070996)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
melanocortin receptor binding	3
cell communication	2
signaling	2
melanin biosynthetic process	2
regulation of melanin biosynthetic process	2
metabolic process	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
feeding behavior	1
adult behavior	1
signal transduction	1
cellular response to hormone stimulus	1
melanosome localization	1
establishment of melanosome localization	1
pigment granule transport	1
pigment granule organization	1
melanin metabolic process	1
secondary metabolite biosynthetic process	1
pigment biosynthetic process	1
phenol-containing compound biosynthetic process	1
epigenetic programming of gene expression	1
negative regulation of secondary metabolite biosynthetic process	1
positive regulation of secondary metabolite biosynthetic process	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
chromatin remodeling	1
regulation of gene expression	1
biological_process	1
protein binding	1
hormone activity	1
neuropeptide activity	1
neuropeptide receptor binding	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASIP	MC1R	Q01726	996
ASIP	POMC	P01189	905
ASIP	AGRP	O00253	825
ASIP	TYRP1	P17643	819
ASIP	OCA2	Q04671	811
ASIP	ATRN	O75882	805
ASIP	RALY	Q9UKM9	801
ASIP	DEFB103A	P81534	800
ASIP	TYR	P14679	782
ASIP	SLC45A2	Q9UMX9	763
ASIP	MC3R	P41968	757
ASIP	AHCY	P23526	756
ASIP	MC4R	P32245	755
ASIP	SLC24A5	Q71RS6	749
ASIP	SLC24A4	Q8NFF2	723

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ASIP	ATRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): GRN (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), APBB2 (Affinity Capture-MS), ATRN (Affinity Capture-MS), SORL1 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), SNX18 (Affinity Capture-MS), ASIP (Negative Genetic)

ESM2 similar proteins: A1YL66, A1YL67, A1YL68, A1YL69, A1YL70, A1YL72, A1YL74, A1YL77, A1YL78, A1YL79, A1YL80, A1YL81, A1YL82, A8CEM0, A8CEM1, A8CEM4, A8CEM5, A8CEM7, A8CEM8, A8CEM9, A8CEN1, A8CEN3, P07467, P42127, P56473, P79407, Q03288, Q1XGU5, Q1XGU6, Q1XGU7, Q1XGU8, Q1XGU9, Q1XGV0, Q1XGV1, Q1XGV2, Q1XGV3, Q1XGV4, Q1XGV5, Q1XGV6, Q1XGV7

Diamond homologs: A1YL66, A1YL67, A1YL68, A1YL69, A1YL70, A1YL72, A1YL74, A1YL77, A1YL78, A1YL79, A1YL80, A1YL81, A1YL82, A8CEM0, A8CEM1, A8CEM4, A8CEM5, A8CEM7, A8CEM8, A8CEM9, A8CEN1, A8CEN3, O00253, P42127, P56413, P56473, P79407, Q03288, Q1XGU5, Q1XGU6, Q1XGU7, Q1XGU8, Q1XGU9, Q1XGV0, Q1XGV1, Q1XGV2, Q1XGV3, Q1XGV4, Q1XGV5, Q1XGV6

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ASIP	“down-regulates activity”	MC1R	binding
ASIP	“down-regulates activity”	MC2R	binding
ASIP	“down-regulates activity”	MC3R	binding
ASIP	“down-regulates activity”	MC4R	binding
ASIP	“down-regulates activity”	MC5R	binding
ASIP	up-regulates	ATRN	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

852 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:34269066:T:A	C100S	0.895
20:34269067:G:C	C100S	0.895
20:34269114:T:A	C116S	0.877
20:34269115:G:C	C116S	0.877
20:34269123:T:C	F119L	0.864
20:34269125:C:A	F119L	0.864
20:34269125:C:G	F119L	0.864
20:34269124:T:G	F119C	0.863
20:34269129:A:C	S121R	0.861
20:34269131:C:A	S121R	0.861
20:34269131:C:G	S121R	0.861
20:34269087:T:A	C107S	0.859
20:34269088:G:C	C107S	0.859
20:34269067:G:A	C100Y	0.858
20:34269087:T:C	C107R	0.856
20:34269108:T:A	C114S	0.854
20:34269109:G:C	C114S	0.854
20:34269089:C:G	C107W	0.851
20:34269088:G:A	C107Y	0.844
20:34269066:T:C	C100R	0.840
20:34269135:T:C	C123R	0.828
20:34269141:T:C	C125R	0.826
20:34269114:T:C	C116R	0.824
20:34269090:T:A	C108S	0.823
20:34269091:G:C	C108S	0.823
20:34269108:T:C	C114R	0.821
20:34269137:C:G	C123W	0.819
20:34269091:G:A	C108Y	0.814
20:34269141:T:A	C125S	0.814
20:34269142:G:C	C125S	0.814

dbSNP variants (sampled 300 via entrez): RS1000030908 (20:34199384 C>T), RS1000123331 (20:34269080 A>C,G), RS1000165443 (20:34188351 G>T), RS1000184697 (20:34244051 T>C), RS1000196849 (20:34188715 T>C), RS1000256337 (20:34249417 G>A), RS1000267754 (20:34203156 CA>C,CAA), RS1000291044 (20:34188511 C>A), RS1000333681 (20:34255025 T>C), RS1000351471 (20:34262378 T>A,C), RS1000391036 (20:34255500 C>T), RS1000442833 (20:34195318 C>T), RS1000518624 (20:34231476 G>C,T), RS1000534535 (20:34209920 C>T), RS1000586833 (20:34252798 G>A)

Disease associations

OMIM: gene MIM:600201 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000193_1	Red vs. non-red hair color	3.000000e-09
GCST000195_1	Skin sensitivity to sun	2.000000e-24
GCST000196_1	Burning and freckling	6.000000e-37
GCST000197_1	Freckles	8.000000e-29
GCST000707_8	Hair color	2.000000e-15
GCST000708_4	Freckling	5.000000e-14
GCST001267_9	Melanoma	1.000000e-07
GCST001683_3	Breast cancer	1.000000e-08
GCST001939_5	Tanning	4.000000e-09
GCST002785_4	Facial pigmentation	3.000000e-09
GCST002906_7	Skin colour saturation	5.000000e-13
GCST002908_1	Skin sensitivity to sun	1.000000e-07
GCST004142_22	Melanoma	5.000000e-23
GCST004219_6	Skin pigmentation	2.000000e-07
GCST004785_56	Vitiligo	1.000000e-19
GCST005896_10	Non-melanoma skin cancer	8.000000e-17
GCST005897_45	Low tan response	1.000000e-315
GCST006585_1879	Blood protein levels	1.000000e-97
GCST007505_24	Nevus count or cutaneous melanoma	5.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0003963	freckles
EFO:0004279	suntan
EFO:0009260	non-melanoma skin carcinoma
EFO:0004632	nevus count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
jinfukang	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	increases expression	1
Rotenone	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.