TYRP1

Summary

TYRP1 (tyrosinase related protein 1, HGNC:12450) is a protein-coding gene on chromosome 9p23, encoding 5,6-dihydroxyindole-2-carboxylic acid oxidase (P17643). Plays a role in melanin biosynthesis.

This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III.

Source: NCBI Gene 7306 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculocutaneous albinism type 3 (Definitive, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 415 total — 42 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12450
Approved symbol	TYRP1
Name	tyrosinase related protein 1
Location	9p23
Locus type	gene with protein product
Status	Approved
Aliases	GP75, CATB, TRP, b-PROTEIN, OCA3
Ensembl gene	ENSG00000107165
Ensembl biotype	protein_coding
OMIM	115501
Entrez	7306

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000381136, ENST00000381142, ENST00000388918, ENST00000459790, ENST00000470909, ENST00000473504, ENST00000473763

RefSeq mRNA: 1 — MANE Select: NM_000550 NM_000550

CCDS: CCDS34990

Canonical transcript exons

ENST00000388918 — 8 exons

Exon	Start	End
ENSE00000689467	12698451	12698655
ENSE00000689470	12707997	12708143
ENSE00001128241	12693385	12693478
ENSE00001487634	12708977	12710285
ENSE00003459626	12693912	12694381
ENSE00003487099	12695515	12695837
ENSE00003606871	12702271	12702438
ENSE00003624211	12704526	12704705

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.95.

FANTOM5 (CAGE): breadth broad, TPM avg 28.2208 / max 8736.8925, expressed in 291 samples.

FANTOM5 promoters (43 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96051	23.3244	138
96061	1.2553	51
96067	0.8470	96
96068	0.3503	86
96069	0.2509	69
96058	0.2106	44
96055	0.1983	32
96079	0.1691	62
96072	0.1421	38
96073	0.1092	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.95	gold quality
upper leg skin	UBERON:0004262	99.36	gold quality
mammalian vulva	UBERON:0000997	98.98	gold quality
penis	UBERON:0000989	98.70	gold quality
upper arm skin	UBERON:0004263	98.08	gold quality
choroid plexus epithelium	UBERON:0003911	97.36	gold quality
skin of hip	UBERON:0001554	97.13	gold quality
nipple	UBERON:0002030	96.81	gold quality
heart right ventricle	UBERON:0002080	96.64	gold quality
left ventricle myocardium	UBERON:0006566	94.29	gold quality
myocardium	UBERON:0002349	93.46	gold quality
zone of skin	UBERON:0000014	89.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.09	gold quality
cardiac ventricle	UBERON:0002082	88.62	gold quality
heart left ventricle	UBERON:0002084	88.57	gold quality
skin of leg	UBERON:0001511	88.50	gold quality
skin of abdomen	UBERON:0001416	87.17	gold quality
corpus epididymis	UBERON:0004359	87.13	gold quality
cardiac atrium	UBERON:0002081	83.99	gold quality
right atrium auricular region	UBERON:0006631	83.68	gold quality
heart	UBERON:0000948	83.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.45	gold quality
apex of heart	UBERON:0002098	81.28	gold quality
nephron tubule	UBERON:0001231	79.95	gold quality
gingiva	UBERON:0001828	76.08	gold quality
biceps brachii	UBERON:0001507	75.93	gold quality
rectum	UBERON:0001052	75.22	gold quality
gall bladder	UBERON:0002110	75.00	gold quality
kidney epithelium	UBERON:0004819	73.87	silver quality
hindlimb stylopod muscle	UBERON:0004252	73.65	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	5450.59
E-MTAB-8142	yes	5093.90
E-ENAD-20	yes	4072.90
E-ANND-2	yes	3582.30
E-GEOD-135922	yes	3326.63
E-MTAB-11121	yes	1649.94
E-ANND-5	yes	748.70
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, KLF15, MITF, NEUROD1, NR4A1, NR4A2, OTX2, PAX3, REST, TBPL1, TBX2, TBXT, TCF4, TFEB, TP53

miRNA regulators (miRDB)

63 targeting TYRP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Tyrp1 is involved in maintaining stability of tyrosinase protein and modulating its catalytic activity. Tyrp1 is also involved in maintenance of melanosome ultrastructure and affects melanocyte proliferation and melanocyte cell death. (PMID:11775055)
• DNA sequence variants in the human TYRP1 gene are not associated with inherited pigmentary glaucoma in humans. (PMID:12011806)
• Data suggest that maintenance of a chronically hyperpigmented phenotype in chronically photoexposed human skin is the result of a stable increase in the number of tyrosinase positive melanocytes at these sites. (PMID:12519123)
• These results suggest that phosphorylation of tyrosinase by PKC-beta induces a complex formation between tyrosinase and TRP-1. (PMID:14623273)
• results shows that organellar pH, proteasome activity, and down-regulation of tyrosinase-related protein 1(TYRP1) expression all contribute to the lack of pigmentation in tyrosinase-positive amelanotic melanoma cells (PMID:14634018)
• We have identified the first TYRP1 mutation in non-Africans and have confirmed that TYRP1 mutations are associated with a milder phenotype of oculocutaneous albinism. (PMID:15996218)
• The presence of a distal Tyrp1 regulatory element, which specifies melanocyte-specific expression, supports the idea that separate regulatory sequences can mediate differential gene expression in melanocytes and RPE. (PMID:16934245)
• Melanocytes in vitiligo demonstrate reduced ability to withstand oxidative stress due, partly, to a disruption in microphthalmia-associated transcription factor regulation of Tyrp1. (PMID:17071589)
• No genetic susceptibility or increased risk attributed to the tyrosinase gene family in Vogt-Koyanagi-Harada disease in Japanese. (PMID:17200659)
• Anemonin, an active compound of C. crassifolia, inhibits melanin synthesis by inhibiting the transcription of the genes encoding TYR, TRP1, and TRP2. (PMID:17766092)
• We observe strong evidence for positive selection for TYRP1 alleles in Africans and in Asians (PMID:18312627)
• Most patients with AROA (autosomal recessive ocular albinism) represent phenotypically mild variants of oculocutaneous albinism , well over half of which is OCA1. (PMID:18326704)
• An eye color variant in TYRP1 was associated with risk of cutaneous melanoma. (PMID:18488027)
• Mutation of TYRP1 (OCA3) can modify the OCA2 phenotype, resulting in red hair. (PMID:18680187)
• TYR is the major OCA (oculocutaneous albinism) gene in Denmark, but several patients do not have mutations in the investigated genes. (PMID:19060277)
• Both TRP-1 and galectin-1 were highly expressed in normal melanocytes and melanoma. There was no correlation between TRP-1 or galectin-1 expression and survival. (PMID:19287070)
• TYRP1 rs1408799 is associated with melanoma. (PMID:19384953)
• Adoptive transfer of TRP1-specific T cells into -expressing recipients produces large confluent patches of vitiligo and ocular damage in TRP1-specific T cell receptor transgenic mice. (PMID:20668223)
• TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation. (PMID:20861488)
• interactions between TRP1-GIPC and GIPC-APPL-AKT provide a potential link between melanogenesis and PI3 kinase signaling (PMID:21291857)
• This review focuses on TYRP1, a melanosomal protein involved in the pigmentary machinery of the melanocyte and often used as differentiation marker, with a special emphasis on its emerging roles in the malignant melanocyte and melanoma progression. (PMID:21324755)
• two novel mutations in TYRP1 gene in two Chinese patients with oculocutaneous albinism type 3 (PMID:21739261)
• Case Report: Report a Japanese girl with oculocutaneous albinism type 3 and novel mutations in TYRP1 gene. (PMID:21996312)
• We used the first ranked gene, tyrosinase-related protein 1 (TYRP1), further measured its expression in the validation population by real-time PCR and found it to be significantly correlated with distant metastasis-free survival. (PMID:22045183)
• 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)
• identifed an arginine-to-cysteine change at a highly conserved residue in TYRP1 as a major determinant of blond hair in Solomon Islanders; this missense mutation predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance (PMID:22556244)
• The results suggested that the miRNAs may be involved in MITF regulation of TYR, TYRP1 and TYRP2, which provides a new clue for understanding the role of miRNAs in melanocyte dysfunctional disease. (PMID:22898827)
• We report four Pakistani albinism mutations, including three SLC45A2 alleles and one 22-nucleotide deletion in TYRP1. (PMID:23190901)
• in human melanoma HMV-II cells both CRF and Ucn1 regulate TRP1 gene expression via Nurr-1/Nur77 production, independent of pro-opiomelanocortin or alpha-melanocyte-stimulating hormone stimulation. (PMID:23416839)
• High TYRP1/S100B mRNA expression in lymph node metastases from melanoma patients is associated with unfavourable clinical outcome. (PMID:23519055)
• Due to mutation in Tyrp1 protein, it became more rigid and might disturb the structural conformation and catalytic function of the structure and might also play a significant role in inducing oculocutaneous albinism type III. (PMID:23862152)
• p53 regulation by TRP2 is not pervasive in melanoma. (PMID:24475287)
• These data indicate that galectin-3 is a regulatory component in melanin synthesis affecting the expression of Tyrp-1. (PMID:25054620)
• These data suggest that UVB-stimulated Ucn1 contributes to TRP1 production via the transcription of both Nurr-1 and Nur77. Ucn1, produced in melanoma cells, acts on melanoma cells themselves in an autocrine manner. (PMID:25240771)
• Single nucleotide polymorphisms in TYRP1 gene is associated with multiple primary melanoma. (PMID:25837821)
• Polymorphisms in 3’UTR of TYRP1 mRNA can affect TYRP1 mRNA regulation by miR-155 and its subsequent translation into protein. These SNPs can render TYRP1 mRNA and protein expression nonsusceptible to miR-155 activity (PMID:26068396)
• Mutation in TYRP1 is associated with oculocutaneous albinism. (PMID:26252096)
• The rs387907171 SNP in TYRP1 exhibits strong allele frequency differences among islands in Northern Island Melanesia. Its absence from Bougainville, as well as the weak association with decreased hair color, indicates that additional alleles contribute to the blondism phenotype. (PMID:26450459)
• DNA sequencing showed that the patient has carried compound heterozygous mutations of the tyrosinase related protein (TYRP1) gene, namely c.1214C>A (p.T405N) and c.1333dupG, which were inherited from his mother and father, respectively. (PMID:28186599)
• catalytic pathway starts with the tyrosinase HsTYR and two tyrosinase-related proteins HsTYRP1 and HsTYRP2. All three enzymes have the same active site but the latter two contain two zinc ions instead of copper ions (PMID:28990327)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tyrp1a	ENSDARG00000029204
danio_rerio	tyrp1b	ENSDARG00000056151
mus_musculus	Tyrp1	ENSMUSG00000005994
rattus_norvegicus	Tyrp1	ENSRNOG00000029318
caenorhabditis_elegans		WBGENE00010060
caenorhabditis_elegans	tyr-4	WBGENE00016419

Paralogs (2): TYR (ENSG00000077498), DCT (ENSG00000080166)

Protein

Protein identifiers

5,6-dihydroxyindole-2-carboxylic acid oxidase — P17643 (reviewed: P17643)

Alternative names: Catalase B, Glycoprotein 75, Melanoma antigen gp75, Tyrosinase-related protein 1

All UniProt accessions (3): P17643, C9JZ52, E7EQI3

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in melanin biosynthesis. Catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into indole-5,6-quinone-2-carboxylic acid in the presence of bound Cu(2+) ions, but not in the presence of Zn(2+). May regulate or influence the type of melanin synthesized. Also to a lower extent, capable of hydroxylating tyrosine and producing melanin.

Subunit / interactions. Monomer. Interacts with ATP7A. Interacts with SLC45A2.

Subcellular location. Melanosome membrane.

Tissue specificity. Pigment cells.

Post-translational modifications. Glycosylated.

Disease relevance. Albinism, oculocutaneous, 3 (OCA3) [MIM:203290] An autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Tyrosinase activity is normal and patients have only moderate reduction of pigment. The eyes present red reflex on transillumination of the iris, dilution of color of iris, nystagmus and strabismus. Darker-skinned individuals have bright copper-red coloration of the skin and hair. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The activity depends critically on the nature of the bound metal ion. Catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the presence of bound Cu(2+) ions, but lacks activity in the presence of bound Zn(2+) ions.

Cofactor. Contains bound zinc ions after heterologous expression in insect cells, giving rise to a protein that lacks DHICA oxidase activity.

Pathway. Pigment biosynthesis; melanin biosynthesis.

Polymorphism. Genetic variants in TYRP1 define the skin/hair/eye pigmentation variation locus 11 (SHEP11) [MIM:612271] and are responsible for variability in hair color linked to chromosome 9p23 in Melanesians. 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.

Similarity. Belongs to the tyrosinase family.

RefSeq proteins (1): NP_000541* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002227	Tyrosinase_Cu-bd	Domain
IPR008922	Di-copper_centre_dom_sf	Homologous_superfamily
IPR050316	Tyrosinase/Hemocyanin	Family

Pfam: PF00264

Catalyzed reactions (Rhea), 1 shown:

• 2 5,6-dihydroxyindole-2-carboxylate + O2 = 2 indole-5,6-quinone-2-carboxylate + 2 H2O (RHEA:68388)

UniProt features (73 total): helix 18, strand 15, disulfide bond 7, turn 7, binding site 6, glycosylation site 6, sequence variant 4, mutagenesis site 3, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
5M8S	X-RAY DIFFRACTION	2.2
9EY8	X-RAY DIFFRACTION	2.2
9EY6	X-RAY DIFFRACTION	2.23
5M8L	X-RAY DIFFRACTION	2.35
5M8T	X-RAY DIFFRACTION	2.35
5M8R	X-RAY DIFFRACTION	2.4
5M8O	X-RAY DIFFRACTION	2.5
5M8N	X-RAY DIFFRACTION	2.6
9EY5	X-RAY DIFFRACTION	2.61
9EY7	X-RAY DIFFRACTION	2.61
5M8M	X-RAY DIFFRACTION	2.65
5M8P	X-RAY DIFFRACTION	2.8
5M8Q	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17643-F1	91.68	0.85

Functional residue map

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

Ligand- & substrate-binding residues (6): 404; 192; 215; 224; 377; 381

Disulfide bonds (7): 30–41, 42–65, 56–99, 101–110, 113–122, 258–261, 290–303

Glycosylation sites (6): 96, 104, 181, 304, 350, 385

Mutagenesis-validated functional residues (3):

Position	Phenotype
362	no effect; when associated with s-374 and v-391.
374	no effect; when associated with f-362 and v-391.
391	no effect; when associated with f-362 and s-374.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5662702	Melanin biosynthesis
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation

MSigDB gene sets: 188 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, JAEGER_METASTASIS_DN, GOBP_VESICLE_ORGANIZATION, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_CELLULAR_PIGMENTATION, MODULE_335, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GRANDVAUX_IRF3_TARGETS_DN, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_UP, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_2_UP, GOBP_PIGMENTATION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (7): melanocyte differentiation (GO:0030318), melanosome organization (GO:0032438), melanin biosynthetic process (GO:0042438), obsolete acetoacetic acid metabolic process (GO:0043438), positive regulation of melanin biosynthetic process (GO:0048023), melanin metabolic process (GO:0006582), pigmentation (GO:0043473)

GO Molecular Function (8): catechol oxidase activity (GO:0004097), tyrosinase activity (GO:0004503), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), identical protein binding (GO:0042802)

GO Cellular Component (10): cytoplasm (GO:0005737), endosome membrane (GO:0010008), clathrin-coated endocytic vesicle membrane (GO:0030669), melanosome membrane (GO:0033162), melanosome (GO:0042470), intracellular vesicle (GO:0097708), membrane (GO:0016020), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), bounding membrane of organelle (GO:0098588)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
pigment cell differentiation	1
pigment granule organization	1
melanin metabolic process	1
secondary metabolite biosynthetic process	1
pigment biosynthetic process	1
phenol-containing compound biosynthetic process	1
melanin biosynthetic process	1
regulation of melanin biosynthetic process	1
positive regulation of secondary metabolite biosynthetic process	1
phenol-containing compound metabolic process	1
secondary metabolic process	1
pigment metabolic process	1
biological_process	1
monooxygenase activity	1
oxidoreductase activity, acting on diphenols and related substances as donors, oxygen as acceptor	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, another compound as one donor, and incorporation of one atom of oxygen	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
oxidoreductase activity	1
binding	1
catalytic activity	1
protein binding	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1
melanosome	1
chitosome	1
pigment granule membrane	1
pigment granule	1
vesicle	1
intracellular membrane-bounded organelle	1
vesicle membrane	1
cytoplasmic vesicle	1
cytoplasm	1

Protein interactions and networks

STRING

2504 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TYRP1	OCA2	Q04671	964
TYRP1	SLC45A2	Q9UMX9	933
TYRP1	MC1R	Q01726	933
TYRP1	MITF	O75030	927
TYRP1	CDK1	P06493	906
TYRP1	SLC24A5	Q71RS6	881
TYRP1	GPR143	P51810	831
TYRP1	RAB38	P57729	823
TYRP1	PMEL	P40967	822
TYRP1	ASIP	P42127	819
TYRP1	GPNMB	Q14956	805
TYRP1	TRPM1	Q7Z4N2	766
TYRP1	CTSB	P07858	765
TYRP1	HPS6	Q86YV9	759
TYRP1	SOX10	P56693	742

IntAct

120 interactions, top by confidence:

A	B	Type	Score
TYRP1	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
ZNF431	TYRP1	psi-mi:“MI:0914”(association)	0.530
GIPC1	TYRP1	psi-mi:“MI:0915”(physical association)	0.510
TYRP1	GIPC1	psi-mi:“MI:0915”(physical association)	0.510
TYRP1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	TYRP1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	TYRP1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
IL16	TYRP1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	TYRP1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
TYRP1	MPP7	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (11): TYRP1 (Affinity Capture-MS), TYRP1 (Affinity Capture-MS), SEC22A (Two-hybrid), TYRP1 (Affinity Capture-MS), TYRP1 (Affinity Capture-MS), GIPC1 (Two-hybrid), GIPC1 (Affinity Capture-Western), RAB11A (Co-fractionation), TF (Co-fractionation), RAB5A (Co-fractionation), HSPA4 (Co-fractionation)

ESM2 similar proteins: A0A142I737, A0A336U966, A0A3B1EFP7, A0A443HK52, A0A8J9R8H5, A0A8J9RRY2, A1CMH6, A1DDD8, A1DLJ5, A2Q7V4, A7BHQ9, A8C7R9, A8NYP0, B0XPZ1, B8NM74, B8NMK3, C7FF04, C7FF05, D4AR77, D4AV38, L0E2Q5, O42713, O93505, P00440, P07147, P0DUQ0, P12031, P17643, P29812, P40126, P56823, P56825, P56826, P80960, P81732, P83040, Q00024, Q0CRX0, Q10584, Q2U1N5

Diamond homologs: O57405, O93505, P07147, P11344, P14679, P17643, P29812, P40126, P54834, P55024, P55025, P55026, P55027, P55028, P55033, Q04604, Q08410, Q0MVP0, Q2VPW6, Q4R1H1, Q8MIU0, Q8WN57, Q95119, Q9BDE0, B1VTI5, P06845, P55023, A0A261GRE4, A0A142I737, A0A336U966, A0A8J9R8H5, A0A8J9RRY2, B8NM74, P07524, P55022, Q0CRX0, Q19673, Q5BGU9, Q9ZP19

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MITF	“up-regulates quantity by expression”	TYRP1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	56.0×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	53.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	53.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	49.8×	4e-13
Dopamine Neurotransmitter Release Cycle	5	48.7×	1e-06
Long-term potentiation	5	46.6×	2e-06
Neurexins and neuroligins	11	42.5×	2e-13
Protein-protein interactions at synapses	7	36.5×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	84.1×	1e-16
protein localization to synapse	6	60.5×	6e-08
receptor clustering	7	57.5×	6e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	45.6×	2e-08
protein-containing complex assembly	9	13.5×	2e-06
cell-cell adhesion	10	13.4×	3e-07
chemical synaptic transmission	8	8.1×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	15
Uncertain significance	186
Likely benign	123
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069699	NM_000550.3(TYRP1):c.82del (p.Arg28fs)	Pathogenic
1407659	NM_000550.3(TYRP1):c.564del (p.Phe188fs)	Pathogenic
1453313	NM_000550.3(TYRP1):c.195T>A (p.Cys65Ter)	Pathogenic
1458626	NM_000550.3(TYRP1):c.418G>T (p.Glu140Ter)	Pathogenic
17594	NM_000550.3(TYRP1):c.497C>G (p.Ser166Ter)	Pathogenic
17597	NM_000550.3(TYRP1):c.107del (p.Ala35_Leu36insTer)	Pathogenic
1912148	NM_000550.3(TYRP1):c.582_585del (p.Tyr193_Tyr194insTer)	Pathogenic
1934514	NM_000550.3(TYRP1):c.325_328dup (p.Cys110Ter)	Pathogenic
1956606	NM_000550.3(TYRP1):c.843dup (p.Val282fs)	Pathogenic
1975781	NM_000550.3(TYRP1):c.474_477del (p.Phe159fs)	Pathogenic
2019995	NM_000550.3(TYRP1):c.716dup (p.Leu239fs)	Pathogenic
2025714	NM_000550.3(TYRP1):c.860_873del (p.Arg287fs)	Pathogenic
2136743	NM_000550.3(TYRP1):c.853C>T (p.Gln285Ter)	Pathogenic
2423316	NC_000009.11:g.(?12693997)(12702458_?)del	Pathogenic
2714033	NM_000550.3(TYRP1):c.3G>T (p.Met1Ile)	Pathogenic
2714280	NM_000550.3(TYRP1):c.744C>G (p.Tyr248Ter)	Pathogenic
2735260	NM_000550.3(TYRP1):c.339C>A (p.Cys113Ter)	Pathogenic
2771899	NM_000550.3(TYRP1):c.48del (p.Leu16fs)	Pathogenic
2791918	NM_000550.3(TYRP1):c.387_422del (p.Arg130_Lys141del)	Pathogenic
2811993	NM_000550.3(TYRP1):c.610G>T (p.Gly204Ter)	Pathogenic
2812409	NM_000550.3(TYRP1):c.173C>G (p.Ser58Ter)	Pathogenic
2813844	NM_000550.3(TYRP1):c.406_407dup (p.Leu136fs)	Pathogenic
2815452	NM_000550.3(TYRP1):c.73C>T (p.Gln25Ter)	Pathogenic
2821508	NM_000550.3(TYRP1):c.237T>A (p.Tyr79Ter)	Pathogenic
2829011	NM_000550.3(TYRP1):c.445del (p.Asp149fs)	Pathogenic
2857933	NM_000550.3(TYRP1):c.899del (p.Gly300fs)	Pathogenic
2859882	NM_000550.3(TYRP1):c.647_668del (p.Glu216fs)	Pathogenic
2865365	NM_000550.3(TYRP1):c.160_161del (p.Asp54fs)	Pathogenic
2866345	NM_000550.3(TYRP1):c.747G>A (p.Trp249Ter)	Pathogenic
2876818	NM_000550.3(TYRP1):c.330_331del (p.Cys110fs)	Pathogenic

SpliceAI

1044 predictions. Top by Δscore:

Variant	Effect	Δscore
9:12698487:T:A	acceptor_gain	1.0000
9:12702266:T:TA	acceptor_gain	1.0000
9:12702267:GCAG:G	acceptor_loss	1.0000
9:12702269:A:AG	acceptor_gain	1.0000
9:12702269:AG:A	acceptor_gain	1.0000
9:12702269:AGGC:A	acceptor_loss	1.0000
9:12702270:G:GT	acceptor_gain	1.0000
9:12702270:GG:G	acceptor_gain	1.0000
9:12702270:GGC:G	acceptor_gain	1.0000
9:12702270:GGCA:G	acceptor_gain	1.0000
9:12702270:GGCAC:G	acceptor_gain	1.0000
9:12702351:G:GT	donor_gain	1.0000
9:12702369:G:GT	donor_gain	1.0000
9:12702443:G:GG	donor_gain	1.0000
9:12704523:TA:T	acceptor_loss	1.0000
9:12704524:AGGT:A	acceptor_loss	1.0000
9:12704702:GCTG:G	donor_gain	1.0000
9:12704703:CTGG:C	donor_loss	1.0000
9:12704704:TGG:T	donor_loss	1.0000
9:12704705:GGTA:G	donor_loss	1.0000
9:12704706:G:GG	donor_gain	1.0000
9:12704707:T:A	donor_loss	1.0000
9:12707992:TTTA:T	acceptor_loss	1.0000
9:12707993:TTA:T	acceptor_loss	1.0000
9:12707994:TA:T	acceptor_loss	1.0000
9:12707995:A:AG	acceptor_gain	1.0000
9:12707996:G:GG	acceptor_gain	1.0000
9:12707996:GAT:G	acceptor_gain	1.0000
9:12707996:GATAT:G	acceptor_gain	1.0000
9:12708013:ATT:A	acceptor_gain	1.0000

AlphaMissense

3544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:12695796:T:A	W223R	0.998
9:12695796:T:C	W223R	0.998
9:12695803:G:T	R225M	0.998
9:12702438:G:C	G361R	0.998
9:12695772:C:G	H215D	0.997
9:12695798:G:C	W223C	0.997
9:12695798:G:T	W223C	0.997
9:12695799:C:G	H224D	0.997
9:12695800:A:C	H224P	0.997
9:12695803:G:C	R225T	0.997
9:12698598:T:A	W286R	0.997
9:12698598:T:C	W286R	0.997
9:12698600:G:C	W286C	0.997
9:12698600:G:T	W286C	0.997
9:12702296:A:C	R313S	0.997
9:12702296:A:T	R313S	0.997
9:12702417:A:C	S354R	0.997
9:12702419:T:A	S354R	0.997
9:12702419:T:G	S354R	0.997
9:12702424:G:C	R356P	0.997
9:12704642:T:C	F400L	0.997
9:12704644:T:A	F400L	0.997
9:12704644:T:G	F400L	0.997
9:12695580:G:C	A151P	0.996
9:12695804:G:C	R225S	0.996
9:12695804:G:T	R225S	0.996
9:12698487:T:A	W249R	0.996
9:12698487:T:C	W249R	0.996
9:12698523:T:A	C261S	0.996
9:12698524:G:C	C261S	0.996

dbSNP variants (sampled 300 via entrez): RS1000003868 (9:12710762 C>G), RS1000034973 (9:12710609 GACTT>G,GACTTACTT), RS1000106710 (9:12701544 G>C,T), RS1000207051 (9:12706198 T>C), RS1000443803 (9:12701131 A>G), RS1000628435 (9:12696205 G>C), RS1000685105 (9:12705881 C>A), RS1000715338 (9:12710680 A>G), RS1000940346 (9:12696338 C>T), RS1001140988 (9:12693246 G>A), RS1001246863 (9:12695996 T>A,C), RS1001813491 (9:12700240 G>A,T), RS1001876820 (9:12704364 T>C), RS1001950223 (9:12704168 G>A), RS1002065780 (9:12702468 G>A,C,T)

Disease associations

OMIM: gene MIM:115501 | disease phenotypes: MIM:203290, MIM:278400

GenCC curated gene-disease

Disease	Classification	Inheritance
oculocutaneous albinism type 3	Definitive	Autosomal recessive

Mondo (2): oculocutaneous albinism type 3 (MONDO:0008747), ocular albinism (MONDO:0017304)

Orphanet (2): Oculocutaneous albinism type 3 (Orphanet:79433), Ocular albinism (Orphanet:284804)

HPO phenotypes

19 total (20 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000635	Blue irides
HP:0000639	Nystagmus
HP:0001000	Abnormality of skin pigmentation
HP:0001010	Hypopigmentation of the skin
HP:0001022	Albinism
HP:0001480	Freckling
HP:0002226	White eyebrow
HP:0002227	White eyelashes
HP:0002297	Red hair
HP:0007443	Partial albinism
HP:0007730	Iris hypopigmentation
HP:0008034	Abnormal iris pigmentation
HP:0009887	Abnormality of hair pigmentation
HP:0011358	Generalized hypopigmentation of hair
HP:0025551	Optic nerve misrouting
HP:0100814	Blue nevus
HP:0200098	Absent skin pigmentation
HP:0001107	Ocular albinism

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000192_1	Blue vs. green eyes	6.000000e-17
GCST001507_1	Hair color	1.000000e-19
GCST001929_5	Eye color	5.000000e-07
GCST002337_84	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST003770_10	Neuroticism	2.000000e-10
GCST005188_2	Skin pigmentation	1.000000e-07
GCST005897_37	Low tan response	1.000000e-17
GCST006075_8	Hair color	5.000000e-67
GCST006988_39	Blond vs. brown/black hair color	1.000000e-77
GCST007323_90	Risk-taking tendency (4-domain principal component model)	1.000000e-09
GCST007327_34	Smoking status (ever vs never smokers)	7.000000e-09
GCST007327_86	Smoking status (ever vs never smokers)	6.000000e-10
GCST007393_5	Mitochondrial DNA copy number	2.000000e-07
GCST007453_1	Eye color	1.000000e-10
GCST007455_2	Eye color (brightness)	5.000000e-16
GCST007457_2	Eye color (saturation)	2.000000e-08
GCST007489_13	Eye color traits	2.000000e-09
GCST007489_7	Eye color traits	2.000000e-10
GCST008096_5	Psoriasis	5.000000e-07
GCST008394_4	Mild to moderate chronic kidney disease	7.000000e-08
GCST009391_1354	Metabolite levels	7.000000e-06
GCST010002_315	Refractive error	1.000000e-11
GCST010148_13	Cutaneous squamous cell carcinoma	4.000000e-08
GCST010302_31	Cutaneous melanoma or hair colour	8.000000e-125
GCST010303_54	Nevus count or cutaneous melanoma	3.000000e-10
GCST010304_62	Cutaneous malignant melanoma	3.000000e-12
GCST010988_388	Adult body size	2.000000e-08
GCST010988_389	Adult body size	4.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color
EFO:0003924	hair color
EFO:0007660	neuroticism measurement
EFO:0004279	suntan
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0006312	mitochondrial DNA measurement
EFO:0009764	eye colour measurement
EFO:0010365	lysophosphatidylcholine 22:6 measurement
EFO:1001927	cutaneous squamous cell carcinoma
EFO:0004632	nevus count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016117	Albinism, Ocular	C11.270.040.090; C16.320.290.040.090; C16.320.565.100.102.090; C16.320.850.080.090; C17.800.621.440.102.090; C17.800.827.080.090; C18.452.648.100.102.090

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712886 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Colforsin	increases expression, decreases reaction, affects cotreatment	3
Resveratrol	decreases expression	2
Valproic Acid	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
testosterone enanthate	affects expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation	1
butylphen	increases expression	1
sodium arsenite	increases expression	1
manganese chloride	decreases expression	1
nickel sulfate	increases expression	1
puerarin	decreases expression	1
epigallocatechin gallate	decreases expression	1
artemisic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
SB 203580	increases expression, decreases reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pomiferin	decreases expression	1
afzelin	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
rosavin	decreases expression	1
bisphenol S	increases methylation	1
cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Vemurafenib	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4732277	Binding	Binding affinity to human tyrosinase related protein 1 expressed in mouse B16F10 cells at 1 uM by fluorophore based flow cytometry assay	Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1. — RSC Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7R5	SEES3-1V human TYRP1, clone1	Embryonic stem cell	Male
CVCL_A7R6	SEES3-1V human TYRP1, clone2	Embryonic stem cell	Male
CVCL_A7R7	SEES3-1V human TYRP1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02200263	Not specified	COMPLETED	The Effects of Lutein and Zeaxanthin Supplementation on Vision in Patients With Albinism