GPNMB

Summary

GPNMB (glycoprotein nmb, HGNC:4462) is a protein-coding gene on chromosome 7p15.3, encoding Transmembrane glycoprotein NMB (Q14956). Could be a melanogenic enzyme.

The protein encoded by this gene is a type I transmembrane glycoprotein which shows homology to the pMEL17 precursor, a melanocyte-specific protein. GPNMB shows expression in the lowly metastatic human melanoma cell lines and xenografts but does not show expression in the highly metastatic cell lines. GPNMB may be involved in growth delay and reduction of metastatic potential. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10457 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyloidosis, primary localized cutaneous, 3 (Definitive, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 176 total — 9 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• MANE Select transcript: NM_002510

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4462
Approved symbol	GPNMB
Name	glycoprotein nmb
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	NMB, HGFIN
Ensembl gene	ENSG00000136235
Ensembl biotype	protein_coding
OMIM	604368
Entrez	10457

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 14 protein_coding, 8 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000258733, ENST00000381990, ENST00000409458, ENST00000459927, ENST00000463011, ENST00000465673, ENST00000468723, ENST00000470994, ENST00000474157, ENST00000478451, ENST00000479625, ENST00000487890, ENST00000492512, ENST00000492858, ENST00000647578, ENST00000878815, ENST00000878816, ENST00000878817, ENST00000878818, ENST00000878819, ENST00000878820, ENST00000963721, ENST00000963722, ENST00000963723, ENST00000963724

RefSeq mRNA: 2 — MANE Select: NM_002510 NM_001005340, NM_002510

CCDS: CCDS34610, CCDS5380

Canonical transcript exons

ENST00000258733 — 11 exons

Exon	Start	End
ENSE00000923996	23259980	23260138
ENSE00001619169	23266517	23266615
ENSE00001709685	23260456	23260773
ENSE00001883505	23246775	23246927
ENSE00001889134	23274065	23275108
ENSE00003540757	23256892	23257065
ENSE00003581501	23267886	23267988
ENSE00003600128	23269967	23270175
ENSE00003628755	23254169	23254312
ENSE00003650937	23253307	23253459
ENSE00003667891	23273521	23273614

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 282.2019 / max 18961.3223, expressed in 1450 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77628	280.3470	1337
77652	0.7080	195
77651	0.4212	162
77649	0.3359	105
77648	0.2148	85
77650	0.1430	54
204383	0.0320	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	99.65	gold quality
skin of hip	UBERON:0001554	99.63	gold quality
tendon of biceps brachii	UBERON:0008188	99.57	gold quality
mammalian vulva	UBERON:0000997	99.48	gold quality
synovial joint	UBERON:0002217	99.39	gold quality
pigmented layer of retina	UBERON:0001782	99.38	gold quality
retina	UBERON:0000966	99.35	gold quality
upper arm skin	UBERON:0004263	99.33	gold quality
skin of abdomen	UBERON:0001416	99.32	gold quality
nipple	UBERON:0002030	99.30	gold quality
gall bladder	UBERON:0002110	99.29	gold quality
layer of synovial tissue	UBERON:0007616	99.26	gold quality
zone of skin	UBERON:0000014	99.22	gold quality
penis	UBERON:0000989	99.17	gold quality
skin of leg	UBERON:0001511	99.06	gold quality
urethra	UBERON:0000057	98.96	gold quality
ectocervix	UBERON:0012249	98.84	gold quality
left ventricle myocardium	UBERON:0006566	98.83	gold quality
stromal cell of endometrium	CL:0002255	98.82	gold quality
descending thoracic aorta	UBERON:0002345	98.82	gold quality
vena cava	UBERON:0004087	98.82	gold quality
endocervix	UBERON:0000458	98.73	gold quality
tendon	UBERON:0000043	98.71	gold quality
heart right ventricle	UBERON:0002080	98.70	gold quality
hair follicle	UBERON:0002073	98.66	gold quality
parietal pleura	UBERON:0002400	98.63	gold quality
mammary duct	UBERON:0001765	98.60	gold quality
pleura	UBERON:0000977	98.57	gold quality
calcaneal tendon	UBERON:0003701	98.41	gold quality
thoracic aorta	UBERON:0001515	98.39	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	2534.80
E-MTAB-6308	yes	2106.13
E-HCAD-15	yes	1621.63
E-GEOD-84465	yes	1072.40
E-GEOD-135922	yes	936.96
E-MTAB-9435	yes	891.95
E-GEOD-75688	yes	502.64
E-HCAD-1	yes	77.00
E-CURD-122	yes	75.88
E-MTAB-10287	yes	29.68
E-MTAB-8142	yes	20.68
E-GEOD-130148	yes	19.48
E-CURD-112	yes	19.17
E-MTAB-9543	yes	17.92
E-HCAD-13	yes	12.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLCN, FNIP2, MITF, MSX2, TFE3, TP53

miRNA regulators (miRDB)

56 targeting GPNMB, 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-3646	100.00	73.56	5283
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8087	99.90	69.55	1351
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-4639-5P	99.81	67.37	1028
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955

Literature-anchored findings (GeneRIF, showing 40)

• Human OA uses the same transcriptional initiation site in both bone and kidney as was reported for melanoma cells and is expressed in osteoblast cultures at all stages of differentiation (PMID:14696968)
• cloning and analysis of two fragments in the 5’ flanking region of HGFIN; studies indicate p53 cooperates with cytokine-mediated transcription factors to regulate the expression of HGFIN (PMID:15684612)
• Osteoactivin is expressed at high levels in normal and inflammatory liver macrophages suggesting a significant role in acute liver injury. (PMID:15763343)
• The GPNMB protein is a potentially useful tumor-associated antigen and prognostic predictor for therapeutic approaches with malignant gliomas or any malignant tumor that expresses GPNMB. (PMID:16609006)
• The results show a central role for p53 in HGFIN expression, which appears to determine the behavior of the cancer cells. (PMID:17845721)
• Osteoactivin was identified as a protein that is expressed in aggressive human breast cancers and is capable of promoting breast cancer metastasis to bone. (PMID:17951401)
• Gpnmb expression can be used as a marker for analyzing melanocyte development and disease progression. (PMID:18983539)
• Gpnmb is a melanosome-associated glycoprotein that contributes to the adhesion of melanocytes with keratinocytes. (PMID:19320736)
• these results solidify the concepts that DC-HIL is a strong negative regulator of APC function and that TGF-beta is a potent stimulator of DC-HIL expression. (PMID:19350579)
• GPNMB is a melanosomal protein that is released by proteolytic ectodomain shedding and might be a useful and specific histological marker of melanocytic cells. (PMID:20056711)
• GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. (PMID:20215530)
• GPNMB expression has a role in uveal melanoma (PMID:20375921)
• ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells (PMID:20711474)
• Toxin-conjugated DC-HIL to abrogate the ability of Sezary syndrome cells to proliferate in vitro. (PMID:21252093)
• GPNMB increase in kidney disease was confirmed by real-time PCR after 5/6 nephrectomy, in streptozotocin-induced diabetes, and in patients with chronic kidney disease (PMID:21389974)
• The abnormal expression of GPNMB may play an important role in the development of prostate cancer. (PMID:21844952)
• upregulated in monocyte-derived dendritic cells by BCR-ABL tyrosine kinase inhibitors (PMID:21874302)
• Gastrointestinal stromal tumours do not show immunopositivity for ERa or HMB45. (PMID:22014058)
• Together these results suggest that GPNMB gene is a p53- and androgen-dysregulated gene and should be regarded as an anti-tumor gene for prostate cancer. (PMID:22290289)
• GPNMB inhibits motor neuron death and plays a critical role in motor neuron survival. (PMID:22891158)
• Silencing of GPNMB by siRNA inhibits the formation of melanosomes in melanocytes in a MITF-independent fashion. (PMID:22912767)
• the molecular basis for the distinct trafficking and morphogenetic properties of PMEL and GPNMB is the PKD domain (PMID:23452376)
• our findings will clarify a new explanation about how GPNMB induces bone repair, and provide a potential target for bone regeneration therapeutics and bone engineering (PMID:23794283)
• GPNMB expression was regulated by EpCAM and CSF-1 partly through their common downstream product c-myc (PMID:23924854)
• GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines. (PMID:24589892)
• Our data identify Gpnmb as a novel marker for obesity-induced adipose tissue macrophage infiltration and potentiator of interleukin-4 responses and point toward a crucial role for MITF in driving part of the adipose tissue macrophage phenotype. (PMID:24789918)
• DC-HIL+ CD14+ HLA-DR no/low cells are a potential blood marker and therapeutic target for melanoma (PMID:24933321)
• GPNMB has protective effect against ischemia-reperfusion injury via phosphorylation of ERK1/2 and Akt (PMID:25010402)
• Glycoprotein nonmetastatic melanoma protein B plays an important role in angiogenesis during hyperoxia injury (PMID:25054912)
• GPNMB/OA protein expression prevents cells from apoptosis-enhancing proliferation and represents a novel modulator of the invasion and metastasis in pancreatic cancer cells. (PMID:25426614)
• GPNMB mRNA in FLCN-related renal cell carcinomas was 23-fold more abundant than in sporadic tumors. (PMID:25594584)
• Data shows that the expression of Gpnmb and Spp1 is highly upregulated in glioma-associated microglia/macrophages highlighting the importance of macrophages and microglia as therapeutic targets in anti-tumor treatment regimens. (PMID:25658639)
• A positive correlation between GPNMB and NRP-1 levels in human breast tumors. (PMID:25772243)
• The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells. (PMID:25889792)
• GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. (PMID:26077887)
• GPNMB plays an important roles in regulating the expression of key pluripotency genes in dental pulp cells and modifying odontogenic differentiation. (PMID:26261527)
• The GPNMB is a promising biomarker and therapeutic target for the development and progression of Nonalcoholic fatty liver disease in obesity. (PMID:26581806)
• Osteoactivin in the extracellular matrix promotes oral squamous carcinoma cell adhesion and migration. (PMID:26636434)
• Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease (PMID:26771826)
• Finally, we identify glycoprotein NMB as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human lymphangioleiomyomatosis samples (PMID:26880751)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpnmb	ENSDARG00000062688
mus_musculus	Gpnmb	ENSMUSG00000029816
rattus_norvegicus	Gpnmb	ENSRNOG00000008816

Paralogs (2): TMEM130 (ENSG00000166448), PMEL (ENSG00000185664)

Protein

Protein identifiers

Transmembrane glycoprotein NMB — Q14956 (reviewed: Q14956)

Alternative names: Hematopoietic growth factor inducible neurokinin-1 type

All UniProt accessions (3): Q14956, A0A3B3ISS6, Q96F58

UniProt curated annotations — full annotation on UniProt →

Function. Could be a melanogenic enzyme.

Subcellular location. Cell membrane. Melanosome membrane. Early endosome membrane.

Tissue specificity. Widely expressed, but very low expression, if any, in the brain. Expressed in the epidermis with higher levels in melanocytes compared with keratinocytes and Langerhans cells (at protein level). Expressed in peripheral blood, but not bone marrow mononuclear cells. Expressed in tissue macrophages, including liver Kuppfer cells and lung alveolar macrophages, in podocytes and in some cells of the ciliary body of the eye (at protein level). May be overexpressed in various cancers, including melanoma and glioblastoma multiforme.

Disease relevance. Increased expression levels in glioblastoma multiforme biopsy samples correlate with poor patient survival prognosis. Has been proposed as a potential target for antibodies coupled to cytotoxic drugs in the context of cancer immunotherapy, including that of melanoma. Amyloidosis, primary localized cutaneous, 3 (PLCA3) [MIM:617920] A primary amyloidosis characterized by localized cutaneous amyloid deposition. This condition usually presents with itching (especially on the lower legs) and visible changes of skin hyperpigmentation and thickening that may be exacerbated by chronic scratching and rubbing. Primary localized cutaneous amyloidosis is often divided into macular and lichen subtypes although many affected individuals often show both variants coexisting. Lichen amyloidosis characteristically presents as a pruritic eruption of grouped hyperkeratotic papules with a predilection for the shins, calves, ankles and dorsa of feet and thighs. Papules may coalesce to form hyperkeratotic plaques that can resemble lichen planus, lichen simplex or nodular prurigo. Macular amyloidosis is characterized by small pigmented macules that may merge to produce macular hyperpigmentation, sometimes with a reticulate or rippled pattern. In macular and lichen amyloidosis, amyloid is deposited in the papillary dermis in association with grouped colloid bodies, thought to represent degenerate basal keratinocytes. The amyloid deposits probably reflect a combination of degenerate keratin filaments, serum amyloid P component, and deposition of immunoglobulins. PLCA3 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by G-CSF/CSF3 and M-CSF/CSF1 in bone marrow mononuclear cells, hence up-regulation may be linked to differentiation.

Similarity. Belongs to the PMEL/NMB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14956-1	1	yes
Q14956-2	2

RefSeq proteins (2): NP_001005340, NP_002501* (*=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: PF18911, PF20433, PF26141

UniProt features (34 total): glycosylation site 12, sequence variant 9, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, modified residue 1, splice variant 1, transmembrane region 1, sequence conflict 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14956-F1	77.05	0.46

Functional residue map

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

Post-translational modifications (1): 542

Glycosylation sites (12): 93, 134, 146, 200, 249, 275, 296, 300, 306, 312, 459, 467

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8857538	PTK6 promotes HIF1A stabilization

MSigDB gene sets: 541 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_52, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, KOBAYASHI_EGFR_SIGNALING_24HR_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, KANG_FLUOROURACIL_RESISTANCE_UP, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION

GO Biological Process (14): negative regulation of cytokine production (GO:0001818), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), negative regulation of cell population proliferation (GO:0008285), positive regulation of cell migration (GO:0030335), negative regulation of tumor necrosis factor production (GO:0032720), regulation of tissue remodeling (GO:0034103), negative regulation of T cell proliferation (GO:0042130), regulation of angiogenesis (GO:0045765), negative regulation of T cell activation (GO:0050868), positive chemotaxis (GO:0050918), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134)

GO Molecular Function (6): integrin binding (GO:0005178), heparin binding (GO:0008201), chemoattractant activity (GO:0042056), syndecan binding (GO:0045545), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), membrane (GO:0016020), early endosome membrane (GO:0031901), melanosome membrane (GO:0033162), endosome (GO:0005768), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by PTK6	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cell communication	2
signaling	2
signaling receptor binding	2
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
tissue remodeling	1
regulation of multicellular organismal process	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
angiogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
T cell activation	1
regulation of T cell activation	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte cell-cell adhesion	1
chemotaxis	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1

Protein interactions and networks

STRING

2336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPNMB	EGFR	P00533	977
GPNMB	PTK6	Q13882	944
GPNMB	TMSB10	P13472	851
GPNMB	TYRP1	P17643	805
GPNMB	ANXA5	P08758	795
GPNMB	SDC4	P31431	775
GPNMB	CD44	P16070	763
GPNMB	COL18A1	P39060	651
GPNMB	LRRK2	Q5S007	634
GPNMB	S100A6	P06703	629
GPNMB	TREM2	Q9NZC2	583
GPNMB	HBEGF	Q99075	575
GPNMB	SNCA	P37840	575
GPNMB	BLK	P51451	554
GPNMB	APOE	P02649	542

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
EGFR	GPNMB	psi-mi:“MI:0915”(physical association)	0.520
GPNMB	PTK6	psi-mi:“MI:0915”(physical association)	0.400
SMAD4	GPNMB	psi-mi:“MI:0915”(physical association)	0.370
	ENO1	psi-mi:“MI:0914”(association)	0.350
IL31RA	DUSP14	psi-mi:“MI:0914”(association)	0.350
C17orf75	MVK	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-RNA), GPNMB (Protein-RNA), GPNMB (Biochemical Activity), GPNMB (Affinity Capture-Western), GPNMB (Affinity Capture-Western), GPNMB (Proximity Label-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS), GPNMB (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QHQ6, A0A3Q1LRJ2, A0A8M9PDM1, B4ER10, B5DFM7, B6ZK77, B8JI67, E1B9E5, E9Q8Q8, E9Q9F6, O35256, O35257, P01241, P01242, P05402, P06880, P08998, P09321, P09586, P09611, P0DJF3, P0DP43, P11228, P18121, P22077, P37886, P58343, P58757, Q0VCB1, Q14406, Q14956, Q5SY80, Q6AXW8, Q6AY06, Q6NXM3, Q6P7C7, Q6P7N7, Q6PVW7, Q6X782, Q6X784

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	6
Uncertain significance	107
Likely benign	19
Benign	10

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2067769	NM_002510.3(GPNMB):c.944_945del (p.Val315fs)	Pathogenic
2577912	NM_002510.3(GPNMB):c.1118-2A>G	Pathogenic
3382241	NM_002510.3(GPNMB):c.393T>G (p.Tyr131Ter)	Pathogenic
503497	NM_002510.3(GPNMB):c.565C>T (p.Arg189Ter)	Pathogenic
503498	NM_002510.3(GPNMB):c.660T>G (p.Tyr220Ter)	Pathogenic
503499	NM_002510.3(GPNMB):c.1056del (p.Pro353fs)	Pathogenic
503500	NM_002510.3(GPNMB):c.296del (p.Asn99fs)	Pathogenic
503501	NM_002510.3(GPNMB):c.719_720del (p.Val240fs)	Pathogenic
503502	NM_002510.3(GPNMB):c.877_880del (p.Val293fs)	Pathogenic
2629416	NM_002510.3(GPNMB):c.701-2A>C	Likely pathogenic
3382360	NM_002510.3(GPNMB):c.807del (p.Pro270fs)	Likely pathogenic
3779708	NM_002510.3(GPNMB):c.1018+1G>A	Likely pathogenic
3779710	NM_002510.3(GPNMB):c.742C>T (p.Arg248Ter)	Likely pathogenic
4845665	NM_002510.3(GPNMB):c.1238G>C (p.Cys413Ser)	Likely pathogenic
983510	NM_002510.3(GPNMB):c.1330C>T (p.Arg444Ter)	Likely pathogenic

SpliceAI

2557 predictions. Top by Δscore:

Variant	Effect	Δscore
15:84657171:CTCA:C	donor_loss	1.0000
15:84657172:TCA:T	donor_loss	1.0000
15:84657173:CA:C	donor_loss	1.0000
15:84657174:ACCTG:A	donor_loss	1.0000
7:23253292:C:CA	acceptor_gain	1.0000
7:23253299:T:A	acceptor_gain	1.0000
7:23253458:GG:G	donor_gain	1.0000
7:23253459:GG:G	donor_gain	1.0000
7:23254312:GGTA:G	donor_loss	1.0000
7:23254313:G:GG	donor_gain	1.0000
7:23254313:GTA:G	donor_loss	1.0000
7:23254314:T:A	donor_loss	1.0000
7:23256890:A:AG	acceptor_gain	1.0000
7:23256891:G:GG	acceptor_gain	1.0000
7:23256891:GA:G	acceptor_gain	1.0000
7:23257046:C:G	donor_gain	1.0000
7:23257084:C:CG	donor_gain	1.0000
7:23259979:GGTCA:G	acceptor_gain	1.0000
7:23267868:T:TA	acceptor_gain	1.0000
7:23267884:A:AG	acceptor_gain	1.0000
7:23267884:AGAG:A	acceptor_gain	1.0000
7:23267884:AGAGG:A	acceptor_gain	1.0000
7:23267885:G:GG	acceptor_gain	1.0000
7:23267885:GAGG:G	acceptor_gain	1.0000
7:23267885:GAGGG:G	acceptor_gain	1.0000
7:23267984:GGGAG:G	donor_gain	1.0000
7:23267985:GGAG:G	donor_gain	1.0000
7:23267985:GGAGG:G	donor_gain	1.0000
7:23267986:GAGG:G	donor_gain	1.0000
7:23269929:T:A	acceptor_gain	1.0000

AlphaMissense

3695 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:23260602:T:A	W283R	0.995
7:23260602:T:C	W283R	0.995
7:23260693:T:C	L313P	0.994
7:23260604:G:C	W283C	0.986
7:23260604:G:T	W283C	0.986
7:23260614:G:C	D287H	0.983
7:23254219:T:C	S92P	0.982
7:23260608:T:C	F285L	0.982
7:23260610:C:A	F285L	0.982
7:23260610:C:G	F285L	0.982
7:23253375:T:A	W47R	0.981
7:23253375:T:C	W47R	0.981
7:23253411:T:G	Y59D	0.981
7:23260073:T:A	V212D	0.980
7:23253396:T:A	W54R	0.979
7:23253396:T:C	W54R	0.979
7:23254195:A:C	S84R	0.979
7:23254197:T:A	S84R	0.979
7:23254197:T:G	S84R	0.979
7:23260487:G:C	Q244H	0.979
7:23260487:G:T	Q244H	0.979
7:23253453:T:A	W73R	0.978
7:23253453:T:C	W73R	0.978
7:23260566:A:C	S271R	0.978
7:23260568:C:A	S271R	0.978
7:23260568:C:G	S271R	0.978
7:23270133:A:C	S475R	0.978
7:23270135:C:A	S475R	0.978
7:23270135:C:G	S475R	0.978
7:23253398:G:C	W54C	0.977

dbSNP variants (sampled 300 via entrez): RS1000155455 (7:23265651 G>T), RS1000257382 (7:23272100 C>T), RS1000308499 (7:23259564 G>A), RS1000405131 (7:23271430 C>G,T), RS1000464118 (7:23267114 T>A,C), RS1000544974 (7:23245161 G>A), RS1000555949 (7:23255746 AT>A), RS1000930457 (7:23256614 C>A), RS1000961541 (7:23248642 G>C), RS1001032337 (7:23254740 G>A), RS1001146733 (7:23254990 G>T), RS1001266224 (7:23248308 C>T), RS1001364022 (7:23262571 C>T), RS1001368757 (7:23247475 C>A), RS1001601943 (7:23253813 G>A)

Disease associations

OMIM: gene MIM:604368 | disease phenotypes: MIM:617920

GenCC curated gene-disease

Disease	Classification	Inheritance
amyloidosis, primary localized cutaneous, 3	Definitive	Autosomal recessive

Mondo (1): amyloidosis, primary localized cutaneous, 3 (MONDO:0054765)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000958	Dry skin
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001034	Hypermelanotic macule
HP:0003621	Juvenile onset
HP:0007440	Generalized hyperpigmentation
HP:0011463	Childhood onset
HP:0020073	Hypopigmented macule

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002544_21	Parkinson’s disease	1.000000e-12
GCST004521_253	Autism spectrum disorder or schizophrenia	6.000000e-11
GCST004824_11	P wave terminal force	6.000000e-10
GCST004824_4	P wave terminal force	4.000000e-09
GCST004902_50	Parkinson’s disease	4.000000e-18
GCST006014_24	Creatine kinase levels	1.000000e-08
GCST006585_1504	Blood protein levels	4.000000e-11
GCST006585_1815	Blood protein levels	8.000000e-11
GCST006585_562	Blood protein levels	5.000000e-24
GCST006585_690	Blood protein levels	4.000000e-23
GCST006585_979	Blood protein levels	1.000000e-19
GCST006803_69	Schizophrenia	9.000000e-10
GCST008103_25	Bipolar disorder	3.000000e-08
GCST009325_43	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	5.000000e-26
GCST010796_1782	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_1783	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST011202_10	Dilated cardiomyopathy (MTAG)	3.000000e-11
GCST011210_5	Dilated cardiomyopathy	8.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008379	P wave terminal force measurement
EFO:0004534	creatine kinase measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712919 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression	8
bisphenol A	decreases expression, increases expression	4
Valproic Acid	decreases expression, increases expression	4
Cyclosporine	decreases expression	4
Doxorubicin	decreases expression, increases expression	3
Estradiol	affects cotreatment, decreases expression, decreases reaction	3
Tretinoin	affects cotreatment, increases expression	3
nickel sulfate	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Arsenic Trioxide	increases expression	2
Cisplatin	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
fluxapyroxad	increases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
beauvericin	affects cotreatment, increases expression	1
chloroacetaldehyde	affects expression	1
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
salinomycin	decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	affects cotreatment, increases expression	1
zinc chromate	increases abundance, increases expression	1
rutecarpine	decreases expression	1
ferrous chloride	increases expression	1

Cellosaurus cell lines

9 cell lines: 5 cancer cell line, 4 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8H0	Abcam HCT 116 GPNMB KO	Cancer cell line	Male
CVCL_B8WE	Abcam MCF-7 GPNMB KO	Cancer cell line	Female
CVCL_B9J9	Abcam A-549 GPNMB KO	Cancer cell line	Male
CVCL_D8M0	Ubigene HCT 116 GPNMB KO	Cancer cell line	Male
CVCL_E1CX	Ubigene THP-1 GPNMB KO	Cancer cell line	Male
CVCL_F1L2	HT809-TH-tdTomato-LysoIP-MitoIP-GBA1 KO/KO + GPNMB KO	Induced pluripotent stem cell	Male
CVCL_F1L3	HT809-TH-tdTomato-LysoIP-MitoIP-GBA1 WT/WT + GPNMB KO	Induced pluripotent stem cell	Male
CVCL_F1L4	HT809-TH-tdTomato-LysoIP-MitoIP-GBA1 L444P/L444P + GPNMB KO	Induced pluripotent stem cell	Male
CVCL_F1L5	HT809-TH-tdTomato-LysoIP-MitoIP + GPNMB KO	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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