PMEL

Summary

PMEL (premelanosome protein, HGNC:10880) is a protein-coding gene on chromosome 12q13.2, encoding Melanocyte protein PMEL (P40967). Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation.

This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 6490 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculocutaneous albinism (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 94 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001384361

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10880
Approved symbol	PMEL
Name	premelanosome protein
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	D12S53E, SI, Pmel17, gp100, HMB-45, ME20, HMB45
Ensembl gene	ENSG00000185664
Ensembl biotype	protein_coding
OMIM	155550
Entrez	6490

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000449260, ENST00000546543, ENST00000547137, ENST00000548493, ENST00000548689, ENST00000548747, ENST00000548803, ENST00000549233, ENST00000549404, ENST00000549413, ENST00000549418, ENST00000549430, ENST00000549564, ENST00000550447, ENST00000550464, ENST00000550590, ENST00000550762, ENST00000552882, ENST00000556802, ENST00000932783, ENST00000932784, ENST00000932785, ENST00000932786

RefSeq mRNA: 6 — MANE Select: NM_001384361 NM_001200053, NM_001200054, NM_001320121, NM_001320122, NM_001384361, NM_006928

CCDS: CCDS55833, CCDS55834, CCDS8897

Canonical transcript exons

ENST00000548747 — 11 exons

Exon	Start	End
ENSE00001300262	55956949	55957671
ENSE00001301477	55955779	55955863
ENSE00001307509	55955274	55955361
ENSE00001321549	55956103	55956219
ENSE00001328498	55955464	55955669
ENSE00002403388	55954105	55954349
ENSE00003489948	55961622	55961732
ENSE00003501001	55957923	55958084
ENSE00003643921	55961317	55961463
ENSE00003663927	55965936	55966042
ENSE00003679126	55958473	55958607

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 95.88.

FANTOM5 (CAGE): breadth broad, TPM avg 43.2747 / max 5987.1608, expressed in 477 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131480	41.3217	268
131481	0.4614	159
131469	0.2199	69
131478	0.1888	60
131472	0.1858	61
131473	0.1810	59
131467	0.1139	46
131468	0.0930	38
131479	0.0922	41
131466	0.0832	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	95.88	gold quality
upper leg skin	UBERON:0004262	94.66	gold quality
mammalian vulva	UBERON:0000997	91.50	gold quality
skin of leg	UBERON:0001511	90.80	gold quality
skin of abdomen	UBERON:0001416	90.66	gold quality
zone of skin	UBERON:0000014	89.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.59	gold quality
ectocervix	UBERON:0012249	83.78	gold quality
penis	UBERON:0000989	82.65	gold quality
upper arm skin	UBERON:0004263	82.22	gold quality
nipple	UBERON:0002030	82.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.49	gold quality
right lobe of liver	UBERON:0001114	77.39	gold quality
body of pancreas	UBERON:0001150	74.45	gold quality
tongue squamous epithelium	UBERON:0006919	74.04	gold quality
lymph node	UBERON:0000029	73.78	gold quality
endocervix	UBERON:0000458	73.08	gold quality
left testis	UBERON:0004533	72.88	gold quality
right testis	UBERON:0004534	72.76	gold quality
body of uterus	UBERON:0009853	72.65	gold quality
frontal pole	UBERON:0002795	72.05	gold quality
mucosa of transverse colon	UBERON:0004991	72.05	gold quality
left ovary	UBERON:0002119	71.91	gold quality
paraflocculus	UBERON:0005351	71.80	gold quality
right ovary	UBERON:0002118	71.78	gold quality
smooth muscle tissue	UBERON:0001135	71.72	gold quality
middle frontal gyrus	UBERON:0002702	71.50	gold quality
rectum	UBERON:0001052	71.36	gold quality
pancreas	UBERON:0001264	71.27	gold quality
testis	UBERON:0000473	71.19	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	8888.42
E-GEOD-135922	yes	6157.01
E-MTAB-7407	yes	5751.08
E-MTAB-8142	yes	3814.83
E-ENAD-20	yes	3741.98
E-MTAB-9435	yes	3016.35
E-MTAB-6108	yes	1839.50
E-GEOD-98556	yes	1544.48
E-MTAB-11121	yes	938.40
E-ANND-5	yes	736.90
E-MTAB-9388	yes	11.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDH3, ELK3, MITF, TAL1, TBPL1

miRNA regulators (miRDB)

12 targeting PMEL, 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-205-3P	99.92	69.92	3165
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-496	98.66	69.80	931
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-637	97.91	64.05	1517

Literature-anchored findings (GeneRIF, showing 40)

• Pmel17 is proteolytically processed in a post-Golgi compartment and is enriched in multivesicular endosomes prior to incorporation in stage II melanosomes. (PMID:11694580)
• we identified the gp100/pMel17 melanosomal protein as the shared antigen recognized by three independent CD8+ CTL clones in HLA-A*6801-restricted fashion. (PMID:12135425)
• A proteolytic fragment of Pmel17, generated by proprotein convertase cleavage, is the major biogenetic component of the underlying fibrillar matrix of melanosome precursors. (PMID:12732614)
• Data show that MITF appears to regulate the expression of the SILV and MLANA genes. (PMID:12819038)
• Antigen-specific T lymphocyte reactivity to gp100 peptides was seen in 15 of 17 (88%) vitiligo patients, with many demonstrating very high reactivity at levels comparable with those observed with common recall antigens (PMID:12925214)
• truncation of the repeat region within Pmel17 alters either fibrillogenic activity or the interaction of Pmel17 with melanin intermediates (PMID:14632201)
• CD8 T lymphocytes recognized a nonameric peptide on melanoma cells that comprises two noncontiguous segments of melanocytic glycoprotein gp100(PMEL17); the production of this peptide involves the excision of four amino acids and splicing of the fragments (PMID:15001714)
• PMEL17 is rapidly processed in the endoplasmic reticulum and glycosylated in the early Golgi (PMID:15096515)
• Data suggest that MART-1 is indispensable for Pmel17 function and thus plays an important role in regulating mammalian pigmentation. (PMID:15695812)
• Details and validates the multiple sorting pathways used by the silver protein to reach melanosomes. It identifies the specific adaptor proteins involved and sheds light on the polarization of the melanocyte. (PMID:16492709)
• Data show that the melanosomal protein Pmel17 is sorted into intralumenal vesicles by a mechanism that is dependent upon lumenal determinants and conserved in non-pigment cells. (PMID:16516837)
• the RPT domain of PMEL17/GP100 is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles (PMID:16682408)
• Pmel17 is a critical component of melanogenesis. (PMID:16704461)
• These data reveal a dual sorting defect in a natural mutant of Pmel17 and support a requirement of endocytic trafficking in Pmel17 fibril formation. (PMID:16760433)
• Detailed analysis of the post-translational modifications and their effect over the processing and trafficking of the silv gene. (PMID:17303571)
• addition of sialic acid affects the stability and sorting of Pmel17 and reduces pigmentation (PMID:17303571)
• GTP-bound form of Rab7 promotes melanogenesis through the regulation of gp100 maturation in melanoma cells. (PMID:17625594)
• Premelanosome amyloid-like fibrils are composed of only golgi-processed forms of Pmel17 that have been proteolytically processed in endosomes (PMID:17991747)
• Measurement of Melan-A, gp100, MAGE-3, MIA and tyrosinase represents a prognostic factor and a method for early detection of metastasis and treatment response of melanoma patients. (PMID:18181974)
• Tyrosinase-, gp100-, or TRP-2-specific CD8(+) T cells could not be identified in the peripheral blood of individuals with vitiligo. (PMID:18337837)
• Nuclear to non-nuclear Pmel17/gp100 expression (HMB45 staining) is a discriminator between benign and malignant melanocytic lesions. (PMID:18552823)
• MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes and is influenced by melanosomes. (PMID:19017974)
• release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position (PMID:19047044)
• the repeat domain of the melanosome fibril protein Pmel17 forms the amyloid core promoting melanin synthesis (PMID:19666488)
• N-terminal domains elicit formation of functional Pmel17 amyloid fibrils. (PMID:19840945)
• Data conclude that sPmel17 is released by regulated proteolytic ectodomain shedding. (PMID:19884326)
• N-terminal region and the polycystic kidney disease-like domain is highly crucial for endoplasmic reticulum export, subcellular targeting, and fibril formation by Pmel17 and thus for establishing functional melanosomes. (PMID:20231267)
• Data suggest that intramelanosomal pH regulates Pmel17 amyloid formation and its subsequent dissolution in vivo. (PMID:21106765)
• Repeat domains of melanosome matrix protein Pmel17 orthologs form amyloid fibrils at the acidic melanosomal pH. (PMID:21148556)
• the multistep processing of Pmel17 begins with an early cleavage during secretion that primes the protein for later functional processing. (PMID:21247888)
• the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. PMEL mutations can model the conversion between physiological and pathological amyloid (PMID:21949659)
• MART-1- and gp100-expressing and -non-expressing melanoma cells are equally proliferative in tumors and clonogenic in vitro. (PMID:21993558)
• This is a review on two human amyloidogenic polypeptides, one associated with Parkinson’s disease, alpha-synuclein (alpha-syn), and the other important for melanin synthesis, the repeat domain (RPT) from Pmel17.[Review] (PMID:21993592)
• Pmel17 repeat domain fibril dissolution is pH dependent (PMID:22092386)
• An antibody drug conjugate reactive with PMEL17 exhibits target-dependent tumor cell killing in vitro and in vivo. (PMID:22613716)
• The most significant single-nucleotide polymorphism in the 12q13.2 locus is located immediately upstream of the promoter region of PMEL for vitiligo in Han Chinese. (PMID:22951725)
• Data indicat that the N-terminal region of PMEL/Pmel17 is essential for the formation of melanosomal fibrils. (PMID:23389629)
• the molecular basis for the distinct trafficking and morphogenetic properties of PMEL and GPNMB is the PKD domain (PMID:23452376)
• The recombinant Pmel 17 plasmids were right as we expected by DNA sequencing (PMID:23643172)
• BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. (PMID:23754390)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pmelb	ENSDARG00000033760
danio_rerio	pmela	ENSDARG00000091298
mus_musculus	Pmel	ENSMUSG00000025359
rattus_norvegicus	Pmel	ENSRNOG00000023085

Paralogs (2): GPNMB (ENSG00000136235), TMEM130 (ENSG00000166448)

Protein

Protein identifiers

Melanocyte protein PMEL — P40967 (reviewed: P40967)

Alternative names: ME20-M, Melanocyte protein Pmel 17, Melanocytes lineage-specific antigen GP100, Melanoma-associated ME20 antigen, P1, P100, Premelanosome protein, Silver locus protein homolog

All UniProt accessions (8): P40967, F8VUB1, F8VXH8, F8VYZ1, F8VZC6, F8VZV2, F8W1D1, H0YIJ2

UniProt curated annotations — full annotation on UniProt →

Function. Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. The maturation of unpigmented premelanosomes from stage I to II is marked by assembly of processed amyloidogenic fragments into parallel fibrillar sheets, which elongate the vesicle into a striated ellipsoidal shape. In pigmented stage III and IV melanosomes, the amyloid matrix serves as a platform where eumelanin precursors accumulate at high local concentrations for pigment formation. May prevent pigmentation-associated toxicity by sequestering toxic reaction intermediates of eumelanin biosynthesis pathway. Represents a potent melanoma-specific antigen. Among melanoma non-mutated self-peptides, G9-154 (KTWGQYWQV), G9-209 (ITDQVPFSV) and G9-280 (YLEPGPVTA), appear to act as immunodominant common epitopes that stimulate anti-tumor immune response mediated by HLA-A-restricted cytotoxic T cells.

Subunit / interactions. Homodimer; disulfide-linked. Dimerization in the endoplasmic reticulum and early Golgi prevents premature fibril formation. The dimers are resolved to monomers in late- or post-Golgi compartments. Heterooligomer; amyloid-type. Processed amyloidogenic fragments assemble into fibrils that further organize into beta-sheet quaternary amyloid structures. Interacts (via luminal C-terminal fragment) with CD63; this is important for sorting of the luminal fragment in tetraspanin rich microdomains in stage I melanosomes to prevent premature lysosomal degradation. Interacts with APOE; this allows the loading of the luminal fragment on ILVs to induce fibril nucleation. Interacts with MLANA.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. cis-Golgi network membrane. Endosome. Multivesicular body. Melanosome. Extracellular vesicle. Secreted.

Tissue specificity. Normally expressed at low levels in quiescent adult melanocytes but overexpressed by proliferating neonatal melanocytes and during tumor growth. Overexpressed in melanomas. Some expression was found in dysplastic nevi.

Post-translational modifications. N- and O-glycosylated. A small amount of P1/P100 (major form) undergoes glycosylation in ER and Golgi compartments to yield P2/P120 (minor form). The mature P2 form leaves the trans-Golgi network and is mainly targeted to stage I melanosomes via the plasma membrane and clathrin-mediated endocytosis. Stage II melanosomes harbor only Golgi-modified fragments that are derived from M-alpha and that bear sialylated O-linked oligosaccharides. O-glycosylation of the RPT region is a conserved feature likely involved in amyloid sheet separation via electrostatic repulsion. Undergoes multiple proteolytic processing. In a post-Golgi prelysosomal compartment, P2 is cleaved by a furin-like proprotein convertase (PC) into two disulfide-linked subunits: a large lumenal subunit, M-alpha/ME20-S, and an integral membrane subunit, M-beta. Despite cleavage, only a small fraction of M-alpha is secreted, as most M-alpha and M-beta remain associated with each other intracellularly via a disulfide bond. Once targeted to stage I melanosomes, beta-secretase BACE2 cleaves the M-beta fragment to release the amyloidogenic luminal fragment containing M-alpha and a small portion of M-beta N-terminus. M-alpha is further cleaved by metalloproteinases, likely ADAM10 or ADAM17, and still unknown proteases to yield subfragments that ultimately assemble into amyloid fibrils. The C-terminal fragment of M-beta is processed by the gamma-secretase complex to release a short intracytoplasmic domain.

Domain organisation. The core amyloid fragment (CAF) represents the amyloidogenic unit of melanosomal fibrils. It is predicted to form a beta-solenoid structure comprising four coil right-handed beta strands with Tyr-151 and Trp-160 residues pi-stacking against each other to confer stability. The highly O-glycosylated repeat (RPT) domain drives the generation of the fibrillar amyloid sheet structures within melanosomes. The O-glycosylation sites rather than its primary amino acid sequence are conserved across species. The Kringle-like domain (KLD) contains six highly conserved cysteine residues that are critical for dimer formation.

Similarity. Belongs to the PMEL/NMB family.

Isoforms (5)

UniProt ID	Names	Canonical?
P40967-1	1, Intermediate form, Pmel17-i	yes
P40967-2	2, Long form, Pmel17-l
P40967-3	3
P40967-4	4, Short form, Pmel17-ls
P40967-5	5, Short form, Pmel17-is

RefSeq proteins (6): NP_001186982, NP_001186983, NP_001307050, NP_001307051, NP_001371290, NP_008859 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000601	PKD_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR022409	PKD/Chitinase_dom	Domain
IPR035986	PKD_dom_sf	Homologous_superfamily
IPR045219	PKAT	Family
IPR046846	PKAT_KLD	Domain
IPR059017	PMEL_NMB_N	Domain

Pfam: PF00801, PF20433, PF26141

UniProt features (105 total): mutagenesis site 52, repeat 12, region of interest 7, site 6, sequence conflict 5, glycosylation site 5, chain 3, splice variant 3, strand 2, disulfide bond 2, topological domain 2, sequence variant 2, signal peptide 1, compositionally biased region 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
5EU5	X-RAY DIFFRACTION	1.54
9JST	ELECTRON MICROSCOPY	1.79
9JSU	ELECTRON MICROSCOPY	1.79
9JSV	ELECTRON MICROSCOPY	1.79
9JSX	ELECTRON MICROSCOPY	1.79
1TVB	X-RAY DIFFRACTION	1.8
1TVH	X-RAY DIFFRACTION	1.8
3CC5	X-RAY DIFFRACTION	1.91
9JSW	ELECTRON MICROSCOPY	1.94
5EU3	X-RAY DIFFRACTION	1.97
5EU6	X-RAY DIFFRACTION	2.02
5EU4	X-RAY DIFFRACTION	2.12
6VM7	X-RAY DIFFRACTION	2.41
6VM8	X-RAY DIFFRACTION	2.41
4IS6	X-RAY DIFFRACTION	2.5
6VMA	X-RAY DIFFRACTION	2.75
6VMC	X-RAY DIFFRACTION	2.85
6VM9	X-RAY DIFFRACTION	2.9
7PHR	ELECTRON MICROSCOPY	3.08
9LIP	ELECTRON MICROSCOPY	3.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40967-F1	69.15	0.35

Functional residue map

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

Catalytic / active sites (6): 151 (essential for fibril formation); 160 (essential for fibril formation); 469–470 (cleavage; by furin-like proprotein convertase); 583–584 (cleavage; by adam metalloproteinases); 655–656 (endocytosis signal); 661 (er exit signal)

Disulfide bonds (2): 301–0, 301–0

Glycosylation sites (5): 81, 106, 111, 321, 568

Mutagenesis-validated functional residues (52):

Position	Phenotype
60	does not affect dimer formation.
130	does not affect dimer formation.
138	does not affect dimer formation.
149	loss-of-function. retained in the endoplasmic reticulum likely due to misfolding.
149	reduces fibril formation.
151	loss-of-function. abolishes fibril formation. does not exert dominant negative effect; when associated with a-211.
151	has normal fibril formation.
152	markedly reduces fibril formation.
153	loss-of-function. abolishes fibrillar amyloid formation. does not exert dominant negative effect and retains the amyloid
154	reduces fibril formation.
155	reduces fibril formation.
156	reduces fibril formation.
157	reduces fibril formation.
158	reduces fibril formation.
159	reduces fibril formation.
160	loss-of-function. abolishes fibril formation. does not exert dominant negative effect; when associated with a-211.
161	reduces fibril formation.
162	reduces fibril formation.
165	reduces fibril formation.
170	loss-of-function. abolishes fibrillar amyloid formation. does not exert dominant negative effect and retains the amyloid
172	loss-of-function. likely misfolded and rapidly degraded.
174	markedly reduces fibril formation. does not exert dominant negative effect; when associated with a-211.
180	reduces fibril formation.
189	loss-of-function. abolishes fibrillar amyloid formation. does not exert dominant negative effect and retains the amyloid
189	has normal fibril formation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 277 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MORF_DNMT1, GOBP_DIGESTION, GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, CCAWYNNGAAR_UNKNOWN, MORF_BUB1, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, REACTOME_DIGESTION_OF_DIETARY_CARBOHYDRATE, MORF_RRM1, GOBP_OLIGOSACCHARIDE_CATABOLIC_PROCESS, GOBP_CELLULAR_PIGMENTATION, MODULE_335

GO Biological Process (3): melanosome organization (GO:0032438), melanin biosynthetic process (GO:0042438), positive regulation of melanin biosynthetic process (GO:0048023)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (14): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), multivesicular body membrane (GO:0032585), cis-Golgi network membrane (GO:0033106), melanosome membrane (GO:0033162), melanosome (GO:0042470), extracellular exosome (GO:0070062), multivesicular body, internal vesicle (GO:0097487), extracellular region (GO:0005576), endosome (GO:0005768), multivesicular body (GO:0005771), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
cytoplasm	2
intracellular membrane-bounded organelle	2
multivesicular body	2
cellular anatomical structure	2
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
protein binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
late endosome membrane	1
cis-Golgi network	1
bounding membrane of organelle	1
melanosome	1
chitosome	1
pigment granule membrane	1
pigment granule	1
extracellular vesicle	1
endosomal intralumenal vesicle	1
cytoplasmic vesicle	1
late endosome	1

Protein interactions and networks

STRING

1789 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PMEL	TYR	P14679	961
PMEL	MLANA	Q16655	959
PMEL	CD8A	P01732	891
PMEL	HLA-A	P01891	883
PMEL	CTAG1A	P78358	857
PMEL	MAGEA3	P43357	857
PMEL	TYRP1	P17643	822
PMEL	CD63	P08962	819
PMEL	DCT	P40126	789
PMEL	CD4	P01730	782
PMEL	GPR143	P51810	775
PMEL	MITF	O75030	762
PMEL	TMSB10	P13472	761
PMEL	MAGEA1	P43355	727
PMEL	CTLA4	P16410	706

IntAct

16 interactions, top by confidence:

A	B	Type	Score
PMEL	PMEL	psi-mi:“MI:0407”(direct interaction)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
PMEL	sepZ	psi-mi:“MI:0915”(physical association)	0.370
ODF2	ELAPOR2	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
GSKIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
GUSB	HOXA3	psi-mi:“MI:0914”(association)	0.350
PMEL	MAN1A2	psi-mi:“MI:0914”(association)	0.350
FOXN3	IGLL5	psi-mi:“MI:0914”(association)	0.350
PEMT	FABP7	psi-mi:“MI:0914”(association)	0.350
PMEL	LRRN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): ATP2A3 (Affinity Capture-MS), TYK2 (Affinity Capture-MS), PMEL (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), C17orf80 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), SLC27A6 (Affinity Capture-MS), ND1 (Affinity Capture-MS), INTS4 (Affinity Capture-MS), CLCN7 (Affinity Capture-MS), MFSD12 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), DNAJC30 (Affinity Capture-MS), GTPBP2 (Affinity Capture-MS), PTPRD (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, D3YX43, D3YZF7, D7PDD4, O70394, O70540, O95866, P01880, P17813, P18627, P22272, P22273, P40223, P40238, P40967, Q00238, Q06154, Q14773, Q15109, Q28173, Q3B8P2, Q495A1, Q5BK54, Q5JXA9, Q5NKT8, Q5R8H1, Q5TJE4, Q60696, Q60837, Q61790, Q61826, Q62151, Q6MG59, Q6PZD2, Q6UWB1, Q7L513, Q7Z442, Q80ZE3, Q86VR7, Q86YW5

Diamond homologs: P40967, Q06154, Q60696, Q98917, Q99P91, Q6P7C7, Q14956, Q90372

SIGNOR signaling

1 interactions.

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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	66
Likely benign	10
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
152934	GRCh38/hg38 12q13.13-13.3(chr12:53420606-56202942)x3	Pathogenic

SpliceAI

2597 predictions. Top by Δscore:

Variant	Effect	Δscore
12:55955463:CCAGG:C	donor_gain	1.0000
12:55955860:CCCT:C	acceptor_gain	1.0000
12:55955861:CCTC:C	acceptor_gain	1.0000
12:55956101:A:AC	donor_gain	1.0000
12:55956102:C:CC	donor_gain	1.0000
12:55958482:T:TA	donor_gain	1.0000
12:55967120:GACAC:G	donor_gain	1.0000
12:55967123:ACGT:A	donor_loss	1.0000
12:55967124:CGT:C	donor_loss	1.0000
12:55967125:G:GG	donor_gain	1.0000
12:55967126:TGAGT:T	donor_loss	1.0000
12:55967127:GAGTG:G	donor_loss	1.0000
12:55967836:T:TA	acceptor_gain	1.0000
12:55967845:A:AG	acceptor_gain	1.0000
12:55967846:A:AG	acceptor_gain	1.0000
12:55967854:A:AG	acceptor_gain	1.0000
12:55967854:AAGT:A	acceptor_gain	1.0000
12:55967855:A:G	acceptor_gain	1.0000
12:55967856:G:GG	acceptor_gain	1.0000
12:55967856:GT:G	acceptor_gain	1.0000
12:55967935:G:GG	donor_gain	1.0000
12:55968046:TA:T	acceptor_loss	1.0000
12:55968047:A:AG	acceptor_gain	1.0000
12:55968047:AG:A	acceptor_gain	1.0000
12:55968047:AGGCT:A	acceptor_gain	1.0000
12:55968048:G:GG	acceptor_gain	1.0000
12:55968048:GG:G	acceptor_gain	1.0000
12:55968048:GGC:G	acceptor_gain	1.0000
12:55968048:GGCT:G	acceptor_gain	1.0000
12:55968048:GGCTG:G	acceptor_gain	1.0000

AlphaMissense

4235 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:55957525:A:G	W260R	0.993
12:55957525:A:T	W260R	0.993
12:55955800:A:G	L512P	0.990
12:55957518:A:C	F262C	0.990
12:55957523:C:A	W260C	0.990
12:55957523:C:G	W260C	0.990
12:55957517:A:C	F262L	0.988
12:55957517:A:T	F262L	0.988
12:55957519:A:G	F262L	0.988
12:55957584:A:G	F240S	0.988
12:55957584:A:C	F240C	0.987
12:55958485:A:G	W153R	0.987
12:55958485:A:T	W153R	0.987
12:55955514:A:G	L571P	0.986
12:55957991:A:T	V188D	0.986
12:55957423:C:G	A294P	0.983
12:55957583:A:C	F240L	0.983
12:55957583:A:T	F240L	0.983
12:55957585:A:G	F240L	0.983
12:55961399:G:C	F84L	0.983
12:55961399:G:T	F84L	0.983
12:55961401:A:G	F84L	0.983
12:55955526:A:G	L567P	0.982
12:55955788:C:G	C516S	0.981
12:55955789:A:G	C516R	0.981
12:55955789:A:T	C516S	0.981
12:55956138:C:G	R479P	0.980
12:55957465:A:C	Y280D	0.980
12:55957989:A:C	Y189D	0.980
12:55957518:A:G	F262S	0.979

dbSNP variants (sampled 300 via entrez): RS1000242782 (12:55954069 C>T), RS1000476732 (12:55964729 G>A,T), RS1000506207 (12:55967895 T>C), RS1000861877 (12:55959003 C>T), RS1000922339 (12:55958296 G>T), RS1001177930 (12:55960982 T>C), RS1001230883 (12:55964129 C>G), RS1001293184 (12:55966775 G>A,C,T), RS1001399238 (12:55958626 G>A,C), RS1001821306 (12:55956704 T>A), RS1002101484 (12:55954736 T>C), RS1002238177 (12:55965675 G>A), RS1002329912 (12:55968053 C>T), RS1002884501 (12:55963078 A>C,T), RS1002902931 (12:55962699 T>A)

Disease associations

OMIM: gene MIM:155550 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
oculocutaneous albinism	Limited	Autosomal recessive

Mondo (1): oculocutaneous albinism (MONDO:0018910)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001670_1	Vitiligo	8.000000e-12
GCST004367_1	Anorexia nervosa	4.000000e-09
GCST006585_1086	Blood protein levels	2.000000e-13
GCST008916_124	Asthma	1.000000e-16
GCST010002_217	Refractive error	6.000000e-174
GCST010703_297	Brain morphology (MOSTest)	4.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016115	Albinism, Oculocutaneous	C11.270.040.545; C16.320.290.040.100; C16.320.565.100.102.100; C16.320.850.080.100; C17.800.621.440.102.100; C17.800.827.080.100; C18.452.648.100.102.100

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712988 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
trichostatin A	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Vemurafenib	increases expression	1
Benzo(a)pyrene	decreases expression	1
Cytarabine	increases expression	1
Dexamethasone	decreases expression, increases expression, affects cotreatment	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	decreases expression	1
Etoposide	affects response to substance	1
Fluoxetine	increases expression	1
Indomethacin	affects cotreatment, decreases expression, increases expression	1
Isothiuronium	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
N-Nitrosopyrrolidine	decreases expression	1
Silicon Dioxide	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5EJ	Quad-GL261	Cancer cell line
CVCL_B8MN	Abcam HCT 116 PMEL KO	Cancer cell line	Male
CVCL_B9PW	Abcam A-549 PMEL KO	Cancer cell line	Male
CVCL_D2GY	Abcam MCF-7 PMEL KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT01663935	PHASE2	TERMINATED	Vision Response to Dopamine Replacement
NCT00467831	PHASE1/PHASE2	TERMINATED	Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
NCT07313618	EARLY_PHASE1	RECRUITING	Safety and Efficacy of a Single Suprachoroidal Injection of JWK010 Gene Therapy in Subjects With Oculocutaneous Albinism Type 1 (OCA1)
NCT00001153	Not specified	COMPLETED	Visual Function and Ocular Pigmentation in Albinism
NCT00808106	Not specified	COMPLETED	Clinical, Cellular, and Molecular Investigation Into Oculocutaneous Albinism
NCT02200263	Not specified	COMPLETED	The Effects of Lutein and Zeaxanthin Supplementation on Vision in Patients With Albinism
NCT04068961	Not specified	COMPLETED	New Strategies of Genetic Study of Patients With Oculocutaneous Albinism
NCT06138509	Not specified	RECRUITING	Peripheral Serotonin and Albinism