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

• Clinical variants (ClinVar): 1 total
• GTEx eGene: eQTL in 7 tissues, sQTL in 4 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.79 (unconstrained)
• 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: 5 — 5 protein_coding

MANE Select: ENST00000374954

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 1

ENST00000374954, ENST00000568305, ENST00000962459, ENST00000962460, ENST00001132240

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.

Highest expression (Bgee): apex of heart, ovary, heart left ventricle, male germ line stem cell (sensu Vertebrata) in testis, cardiac ventricle.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASIP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	1.6e-19	-0.59	20:34077942:A:G
Skin Sun Exposed Lower leg	eqtl	1.5e-18	+0.54	20:33917852:G:C
Nerve Tibial	eqtl	4.8e-12	+0.53	20:33917852:G:C
Nerve Tibial	sqtl	1.2e-07	+0.74	20:34648892:G:C
Skin Not Sun Exposed Suprapubic	sqtl	8.7e-04	+0.63	20:33917852:G:C
Skin Sun Exposed Lower leg	sqtl	1.1e-03	+0.55	20:33917852:G:C
Adipose Subcutaneous	eqtl	4.1e-03	+0.72	20:34316608:G:A
Brain Cortex	eqtl	9.4e-03	-0.59	20:34077942:A:G
Testis	sqtl	9.5e-03	-1.28	20:33255007:T:G
Breast Mammary Tissue	eqtl	2.4e-02	+0.42	20:34204408:G:C
Brain Spinal cord cervical c-1	eqtl	3.5e-02	-1.09	20:34067706:C:T

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

showing 100 of 289 tissues 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
right lung	UBERON:0002167	59.12	gold quality
caput epididymis	UBERON:0004358	59.08	silver quality
endometrium epithelium	UBERON:0004811	59.00	gold quality
right adrenal gland cortex	UBERON:0035827	58.26	gold quality
gastrocnemius	UBERON:0001388	58.17	gold quality
left adrenal gland cortex	UBERON:0035825	58.12	gold quality
female reproductive system	UBERON:0000474	57.98	gold quality
right adrenal gland	UBERON:0001233	57.80	gold quality
leukocyte	CL:0000738	57.70	gold quality
right uterine tube	UBERON:0001302	57.51	gold quality
ectocervix	UBERON:0012249	57.51	gold quality
uterine cervix	UBERON:0000002	57.39	gold quality
left adrenal gland	UBERON:0001234	57.34	gold quality
subcutaneous adipose tissue	UBERON:0002190	57.31	gold quality
mucosa of stomach	UBERON:0001199	57.20	gold quality
adrenal cortex	UBERON:0001235	56.90	gold quality
minor salivary gland	UBERON:0001830	56.09	gold quality
metanephros cortex	UBERON:0010533	55.52	gold quality
muscle of leg	UBERON:0001383	55.25	gold quality
ileal mucosa	UBERON:0000331	55.24	silver quality
adenohypophysis	UBERON:0002196	54.98	gold quality
prostate gland	UBERON:0002367	54.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	54.36	gold quality
cerebellar vermis	UBERON:0004720	54.35	gold quality
mouth mucosa	UBERON:0003729	54.28	gold quality
omental fat pad	UBERON:0010414	53.93	gold quality
peritoneum	UBERON:0002358	53.89	gold quality
uterus	UBERON:0000995	53.70	gold quality
muscle organ	UBERON:0001630	53.61	gold quality
adrenal gland	UBERON:0002369	53.24	gold quality
adipose tissue of abdominal region	UBERON:0007808	53.20	gold quality
myometrium	UBERON:0001296	53.12	gold quality
fallopian tube	UBERON:0003889	53.06	gold quality
small intestine Peyer’s patch	UBERON:0003454	53.05	gold quality
left testis	UBERON:0004533	52.82	gold quality
right testis	UBERON:0004534	52.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	52.73	gold quality
metanephros	UBERON:0000081	52.70	gold quality
vagina	UBERON:0000996	52.42	gold quality
adipose tissue	UBERON:0001013	52.34	gold quality
adult mammalian kidney	UBERON:0000082	52.29	gold quality
nasal cavity mucosa	UBERON:0001826	52.10	gold quality
liver	UBERON:0002107	52.06	gold quality
saliva-secreting gland	UBERON:0001044	51.88	gold quality
connective tissue	UBERON:0002384	51.86	gold quality
sigmoid colon	UBERON:0001159	51.78	gold quality
spinal cord	UBERON:0002240	51.64	gold quality
left coronary artery	UBERON:0001626	51.36	gold quality
testis	UBERON:0000473	51.35	gold quality
fundus of stomach	UBERON:0001160	51.34	gold quality
upper leg skin	UBERON:0004262	51.25	silver quality
upper arm skin	UBERON:0004263	51.14	gold quality
tibialis anterior	UBERON:0001385	51.13	silver quality
mucosa of transverse colon	UBERON:0004991	51.07	gold quality
epithelial cell of pancreas	CL:0000083	51.06	gold quality
deltoid	UBERON:0001476	50.96	gold quality
cortex of kidney	UBERON:0001225	50.61	gold quality
quadriceps femoris	UBERON:0001377	50.58	gold quality
anatomical system	UBERON:0000467	50.44	gold quality
multicellular organism	UBERON:0000468	50.31	gold quality
small intestine	UBERON:0002108	50.31	gold quality
material anatomical entity	UBERON:0000465	50.30	gold quality
endometrium	UBERON:0001295	50.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	49.86	gold quality
left lobe of thyroid gland	UBERON:0001120	49.80	gold quality
calcaneal tendon	UBERON:0003701	49.60	gold quality
coronary artery	UBERON:0001621	49.51	gold quality
adrenal tissue	UBERON:0018303	49.39	silver quality
vastus lateralis	UBERON:0001379	49.32	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	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

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 140 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	56.4
Skin 1	tissue	46.1	low
Esophagus	tissue	44.9	medium
Hippocampal formation	tissue	44.6
Spinal cord	tissue	43.1
Hypothalamus	tissue	39.7
Periaqueductal gray	tissue	38.9
Basal ganglia	tissue	36.8	low
Ventral forebrain	tissue	36.7
Hippocampus	tissue	36.6	not detected
Putamen	tissue	35.9
Medulla oblongata	tissue	35.7
Substantia nigra	tissue	35.5
Nucleus accumbens	tissue	35.4
Superior colliculi	tissue	35.0
Choroid plexus	tissue	34.8
Midbrain	tissue	33.5
Pons	tissue	32.3
Pancreas	tissue	32.2	medium
Thalamus	tissue	32.1
Septum	tissue	31.7
Ovary	tissue	30.6	not detected
Locus coeruleus	tissue	30.0
Skeletal muscle	tissue	28.9	not detected
Tongue	tissue	28.8
Vagina	tissue	28.1	low
Amygdala	tissue	25.5
Kidney	tissue	23.4	medium
Seminal vesicle	tissue	22.5	not detected
Olfactory bulb	tissue	22.4
Caudate putamen	tissue	21.8
Liver	tissue	20.7	low
Rectum	tissue	20.4	medium
Smooth muscle	tissue	20.4	not detected
Placenta	tissue	20.4	low
Cerebellum	tissue	20.2	medium
Breast	tissue	20.1	low
Cerebral cortex	tissue	19.8	medium
Retrosplenial cortex	tissue	19.8
Parathyroid gland	tissue	19.5	not detected
Fallopian tube	tissue	19.4	medium
Endometrium 1	tissue	19.3	medium
Insular cortex	tissue	19.0
Motor cortex	tissue	18.0
Colon	tissue	17.7	medium
Retrosplenial and cingulate cortex	tissue	17.7
Temporal cortex	tissue	17.6
Entorhinal cortex	tissue	17.4
Prefrontal cortex	tissue	17.0
Urinary bladder	tissue	17.0	medium
Somatosensory cortex	tissue	16.1
Prostate	tissue	15.9	not detected
Cervix	tissue	15.3	not detected
Occipital cortex	tissue	15.2
Postcentral gyrus	tissue	14.9
Lung	tissue	14.3	medium
Thyroid gland	tissue	14.2	low
Gallbladder	tissue	14.0	medium
Salivary gland	tissue	13.8	low
Testis	tissue	13.1	medium

Brain sub-regions (HPA Brain Atlas): detected in 381; highest nTPM — White matter (56.4), Ventromedial nucleus (51.5), Periaquaductal grey, dorsal (48.1), Dorsal hippocampus (44.6), Arcuate nucleus (44.2).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 1.77e-05, LOEUF 1.79, missense Z -0.54 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000374954 — one region, missense o/e 1.06.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87853) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 62 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal coat/hair pigmentation	24
abnormal ventral coat pigmentation	11
yellow coat color	10
darkened coat color	8
irregular coat pigmentation	4
mottled coat	4
obese	4
abnormal dorsoventral coat patterning	4
abnormal pinna hair pigmentation	4
abnormal coat appearance	3
prenatal lethality	3
maternal effect	3
variegated coat color	2
increased susceptibility to weight gain	2
embryonic lethality	2
abnormal epigenetic regulation of gene expression	2
increased brown adipose tissue amount	1
increased body length	1
increased body weight	1
cataract	1
decreased locomotor activity	1
hyperglycemia	1
increased urine glucose level	1
increased tumor incidence	1
decreased incidence of induced tumors	1

+37 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca sylvanus	A1YL66	100.0%	Diamond
Macaca mulatta	A1YL67	100.0%	Diamond
Macaca nemestrina	A1YL69	100.0%	Diamond
Papio anubis	A1YL70	100.0%	Diamond
Trachypithecus auratus	A1YL72	100.0%	Diamond
Trachypithecus francoisi	A1YL74	100.0%	Diamond
Callithrix jacchus	A1YL77	100.0%	Diamond
Callithrix geoffroyi	A1YL78	100.0%	Diamond
Callimico goeldii	A1YL80	100.0%	Diamond
Leontopithecus chrysomelas	A1YL81	100.0%	Diamond
Leontopithecus rosalia	A1YL82	100.0%	Diamond
Macaca fuscata fuscata	A8CEM0	100.0%	Diamond
Macaca maura	A8CEM4	100.0%	Diamond
Macaca arctoides	A8CEM9	100.0%	Diamond
Macaca sinica	A8CEN1	100.0%	Diamond
Trachypithecus cristatus	Q1XGU6	100.0%	Diamond
Trachypithecus obscurus	Q1XGU7	100.0%	Diamond
Erythrocebus patas	Q1XGV0	100.0%	Diamond
Chlorocebus aethiops	Q1XGV1	100.0%	Diamond
Macaca radiata	Q1XGV2	100.0%	Diamond
Macaca fascicularis	Q1XGV3	100.0%	Diamond
Gorilla gorilla gorilla	Q1XGV5	100.0%	Diamond
Pan paniscus	Q1XGV6	100.0%	Diamond
Pan troglodytes	Q1XGV7	100.0%	Diamond
Macaca nigra	A1YL68	99.2%	Diamond
Macaca cyclopis	A8CEM1	99.2%	Diamond
Macaca hecki	A8CEM5	99.2%	Diamond
Macaca silenus	A8CEM8	99.2%	Diamond
Macaca assamensis	A8CEN3	99.2%	Diamond
Cercopithecus mitis	Q1XGU9	99.2%	Diamond
Macaca nigrescens	A8CEM7	98.5%	Diamond
Colobus polykomos	Q1XGU5	98.5%	Diamond
Semnopithecus entellus	Q1XGU8	98.5%	Diamond
Vulpes vulpes	P79407	97.7%	Diamond
Canis lupus familiaris	Q5UK76	97.7%	Diamond
Cebuella pygmaea	A1YL79	97.0%	Diamond
Pongo pygmaeus	Q1XGV4	95.5%	Diamond
Bos taurus	P56413	84.3%	Diamond
Sus scrofa	Q9TU18	84.3%	Diamond
Equus caballus	Q95MP2	83.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
AHCY	protein-coding	191
EIF2S2	protein-coding	8894
MIR4755	ncRNA	100616434
RALY-AS1	ncRNA	101926888
RALY	protein-coding	22913
ITCH	protein-coding	83737
MIR644A	ncRNA	693229
DYNLRB1	protein-coding	83658
MAP1LC3A	protein-coding	84557

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 (18 total): disulfide bond 5, strand 5, 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 by resolution:

PDB	Title	Method	Resolution (Å)
1Y7J	NMR structure family of Human Agouti Signalling Protein (80-132: Q115Y, S124Y)	SOLUTION NMR
1Y7K	NMR structure family of Human Agouti Signalling Protein (80-132: Q115Y, S124Y)	SOLUTION NMR
2KZA	Solution structure of ASIP(80-132, P103A, P105A, Q115Y, S124Y)	SOLUTION NMR
2L1J	1H assignments for ASIP(93-126, P103A, P105A, P111A, Q115Y, S124Y)	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted secreted proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; flagellar centriole; mid piece

Antibody reliability (HPA): IH uncertain · IF approved

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)

Type	Positions
Disulfide bond	116–123, 93–108, 100–114, 107–125, 111–132

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	39

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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 (9): generation of precursor metabolites and energy (GO:0006091), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), hormone-mediated signaling pathway (GO:0009755), melanosome organization (GO:0032438), melanin biosynthetic process (GO:0042438), 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)

GO Molecular Function (5): signaling receptor binding (GO:0005102), neuropeptide hormone activity (GO:0005184), melanocortin receptor binding (GO:0031779), receptor antagonist activity (GO:0048019), type 1 melanocortin receptor binding (GO:0070996)

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

28 GO namespaces:

Category	Terms
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
signal transduction	1
cellular response to hormone stimulus	1
pigment granule organization	1
melanin metabolic process	1
secondary metabolite biosynthetic process	1
pigment biosynthetic process	1
phenol-containing compound biosynthetic process	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
protein binding	1
hormone activity	1
neuropeptide activity	1
neuropeptide receptor binding	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
melanocortin receptor binding	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 16 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of melanin biosynthetic process	BP	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 544 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASIP	MC1R	Q01726	979
ASIP	POMC	P01189	846
ASIP	TYRP1	P17643	831
ASIP	AGRP	O00253	822
ASIP	OCA2	Q04671	802
ASIP	RALY	Q9UKM9	782
ASIP	TYR	P14679	778
ASIP	SLC24A5	Q71RS6	763
ASIP	MC4R	P32245	760
ASIP	MC3R	P41968	758
ASIP	AHCY	P23526	744
ASIP	SLC45A2	Q9UMX9	741
ASIP	SLC24A4	Q8NFF2	725
ASIP	DEFB103A	P81534	696
ASIP	SDC3	O75056	695

IntAct

Human interaction partners of ASIP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ATRN	association	0.350	1

BioGRID (9 interactions; top human partners by supporting records): APBB2 (Affinity Capture-MS), ATRN (Affinity Capture-MS), C16orf72 (Negative Genetic), GRN (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), SNX18 (Affinity Capture-MS), SORL1 (Affinity Capture-MS)

SIGNOR signaling

showing 6 of 7 signaling 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

Genetic variants

Variant evidence for ASIP: 1 ClinVar records (0 pathogenic / likely pathogenic).

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

AlphaMissense

100 missense substitutions predicted likely pathogenic (of 852 scored), across 21 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
C100	7	0.820	0.895
F119	7	0.816	0.864
C107	7	0.812	0.859
C114	7	0.786	0.854
C116	7	0.784	0.877
C108	7	0.757	0.823
C125	7	0.745	0.826
C111	7	0.737	0.812
C93	7	0.708	0.774
C123	6	0.791	0.828
S121	6	0.764	0.861
C132	6	0.714	0.799
F118	5	0.715	0.723
S99	3	0.692	0.692
S22	3	0.611	0.611
K101	2	0.686	0.686
K57	2	0.616	0.616
C16	1	0.704	0.704
V13	1	0.637	0.637
A112	1	0.632	0.632

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

7 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	2.23e-06
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	6.1e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000107
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	0.000122
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000234
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000827
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000959

Disease associations

OMIM: gene MIM:600201 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

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)

Via MONDO — disease-level, not drug-specific.