CD109

Summary

CD109 (CD109 molecule, HGNC:21685) is a protein-coding gene on chromosome 6q13, encoding CD109 antigen (Q6YHK3). Modulates negatively TGFB1 signaling in keratinocytes.

This gene encodes a glycosyl phosphatidylinositol (GPI)-linked glycoprotein that localizes to the surface of platelets, activated T-cells, and endothelial cells. The protein binds to and negatively regulates signalling by transforming growth factor beta (TGF-beta). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 135228 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 287 total — 2 pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_133493

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21685
Approved symbol	CD109
Name	CD109 molecule
Location	6q13
Locus type	gene with protein product
Status	Approved
Aliases	HPA-15, FLJ38569, DKFZp762L1111, CPAMD7
Ensembl gene	ENSG00000156535
Ensembl biotype	protein_coding
OMIM	608859
Entrez	135228

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000287097, ENST00000422508, ENST00000437994, ENST00000474094, ENST00000649530

RefSeq mRNA: 3 — MANE Select: NM_133493 NM_001159587, NM_001159588, NM_133493

CCDS: CCDS4982, CCDS55038, CCDS55039

Canonical transcript exons

ENST00000287097 — 33 exons

Exon	Start	End
ENSE00001027065	73810992	73811147
ENSE00001027067	73809984	73810174
ENSE00001027071	73814981	73815123
ENSE00001027079	73820461	73820563
ENSE00001027080	73818388	73818535
ENSE00001084367	73697400	73697572
ENSE00001084371	73723251	73723279
ENSE00001084377	73730344	73730574
ENSE00001084387	73792626	73792802
ENSE00001084395	73808083	73808248
ENSE00001084398	73806844	73807072
ENSE00001084417	73787234	73787452
ENSE00001084418	73785364	73785477
ENSE00001084424	73788468	73788612
ENSE00001144154	73812205	73812270
ENSE00001144223	73783707	73783824
ENSE00001144229	73782614	73782755
ENSE00001144235	73781259	73781319
ENSE00001144243	73780424	73780498
ENSE00001144250	73771429	73771581
ENSE00001144259	73768055	73768231
ENSE00001144267	73766948	73767010
ENSE00001144274	73766759	73766860
ENSE00001144282	73765930	73766154
ENSE00001144291	73763576	73763685
ENSE00001144299	73762741	73762882
ENSE00001144307	73762384	73762480
ENSE00001144318	73758944	73759028
ENSE00001144326	73756643	73756682
ENSE00001144336	73736383	73736508
ENSE00001918330	73696203	73696289
ENSE00001928103	73823458	73828313
ENSE00003553744	73803220	73803301

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.8171 / max 608.7397, expressed in 1618 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68594	32.2406	1575
68588	2.7237	671
68593	2.6293	1027
68586	2.4186	915
68592	1.2228	667
68590	0.6649	402
68591	0.3729	210
68598	0.2055	49
68604	0.1690	79
68587	0.1066	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.43	gold quality
upper arm skin	UBERON:0004263	98.49	gold quality
upper leg skin	UBERON:0004262	96.28	gold quality
skin of hip	UBERON:0001554	96.24	gold quality
layer of synovial tissue	UBERON:0007616	95.87	gold quality
mammalian vulva	UBERON:0000997	95.67	gold quality
tendon of biceps brachii	UBERON:0008188	95.56	gold quality
cartilage tissue	UBERON:0002418	94.30	gold quality
nipple	UBERON:0002030	94.12	gold quality
gingiva	UBERON:0001828	93.54	gold quality
calcaneal tendon	UBERON:0003701	93.19	gold quality
gingival epithelium	UBERON:0001949	93.03	gold quality
stromal cell of endometrium	CL:0002255	92.82	gold quality
penis	UBERON:0000989	92.77	gold quality
buccal mucosa cell	CL:0002336	92.62	silver quality
tendon	UBERON:0000043	92.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.61	gold quality
synovial joint	UBERON:0002217	92.45	gold quality
visceral pleura	UBERON:0002401	91.92	gold quality
parietal pleura	UBERON:0002400	91.81	gold quality
kidney epithelium	UBERON:0004819	91.13	gold quality
urethra	UBERON:0000057	90.92	gold quality
amniotic fluid	UBERON:0000173	90.49	gold quality
saphenous vein	UBERON:0007318	90.06	gold quality
pharyngeal mucosa	UBERON:0000355	89.89	gold quality
esophagus squamous epithelium	UBERON:0006920	89.00	gold quality
endothelial cell	CL:0000115	88.66	gold quality
left ventricle myocardium	UBERON:0006566	87.37	gold quality
smooth muscle tissue	UBERON:0001135	86.61	gold quality
oral cavity	UBERON:0000167	86.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	14.60
E-MTAB-10290	no	404.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

183 targeting CD109, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. cDNA sequence determination and protein structure analysis given. (PMID:11861284)
• A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. (PMID:11861285)
• Findings suggest that CD109 may become a molecular target for the development of new therapeutics for squamous cell carcinoma of various tissue origins. (PMID:15826242)
• CD109 plays a unique role in the regulation of isoform-specific TGF-beta signaling in keratinocytes. (PMID:16754747)
• Found with a mutation in 7% of colon cancers studied. (PMID:16959974)
• Findings indicate that CD109 is a useful marker for the diagnosis of invasive breast and prostate carcinomas. (PMID:17493171)
• the novel gene HEPT3 may function through its noncoding RNA and its overexpression may play a role in hepatocarcinogenesis [HEPT3] (PMID:17611685)
• CD109 expression may play a role in the development of lung squamous cell carcinoma. (PMID:17922683)
• Up-regulation of CD109 expression is associated with carcinogensis of the squamous epithelium of the oral cavity. (PMID:19016750)
• Report PRSS3/mesotrypsin upregulation in breast cancer cells and identify CD109 as the functional proteolytic target of mesotrypsin. (PMID:20035377)
• Processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes. (PMID:20101215)
• These findings suggest that CD109 is involved in bladder tumorigenesis and is a potential target for cancer immunotherapy. (PMID:20946523)
• CD109 regulates TGF-beta receptor endocytosis and degradation to inhibit TGF-beta signaling. (PMID:21295082)
• CD109 release from the cell surface in human keratinocytes regulates TGF-beta receptor expression, TGF-beta signalling and STAT3 activation. (PMID:21539622)
• CD109 is an important regulator of SMAD7/Smurf2-mediated degradation of TGFBR1. (PMID:21898545)
• The upregulation of CD109 protein in SSc may represent an adaptation or consequence of aberrant TGF-beta signaling in systemic sclerosis (PMID:22694813)
• expression of CD109 (human platelet antigen 15) mRNA is different in various human cell types (PMID:23509816)
• High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancer-initiating cells in a novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma. (PMID:24376795)
• Hematopoietic cell marker CD109 is expressed in hepatic progenitor cells. (PMID:24396288)
• CD109 plays a critical role in non-small-cell lung cancer (NSCLC) progression, and is overexpressed in advanced NSCLC (PMID:24667143)
• CD109 is highly expressed in TNBC and is a potential biomarker for the initiation, progression, and differentiation of breast cancer tumors. (PMID:25149155)
• expression increased in cutaneous squamous cell carcinoma (PMID:25271095)
• CD109 is specifically expressed in endothelial cells of cutaneous cavernous haemangioma. (PMID:25388101)
• The results suggest that circulating endothelial cells express CD109 and represent a rare population of circulating tumor endothelial cells, that play a potentially useful prognostic role in patients with glioblastoma. (PMID:25506915)
• Three glioblastoma cell lines, SK-MG-1, U251MG and MG178, were tested and CD109 overexpression attenuated TGF-beta1 signaling and enhanced EGF signaling in SK-MG-1, but not in U251MG or MG178. (PMID:25724945)
• CD109 overexpression was significantly associated with surgical stage, distant metastasis, and poor prognosis in myxofibrosarcoma. (PMID:26031650)
• findings show elevated CD109 protein expression in esophageal squamous cell carcinoma (ESCC); CD109 expression is restricted in squamous cells of ESCCs (PMID:26122747)
• CD109 may be a potential pathology marker for gallbladder squamous cell/adenosquamous carcinomas. (PMID:26249215)
• sCD109 can bind TGF-beta, inhibit TGF-beta binding to its receptors and decrease TGF-beta signalling and TGF-beta-induced cellular responses. (PMID:26621871)
• These findings indicate that CD109 is an exosomal protein and that the C-terminal region of CD109 is required for its presence in the exosome. (PMID:26707640)
• Expression levels of CD109 was reduced significantly in psoriasis. Lower expression of CD109 and TGF-beta RI was highly correlated with higher expression of Smad7 and Ki67, suggesting that CD109 may induce the pathogenesis of psoriasis through Smad7-mediated degradation of TGF-beta RI. (PMID:26838754)
• The most common HPA genotypes among Saudis were HPA-1 a + b- (75%), HPA-2 a + b- (62%), HPA-3 a + b- (51.5%), HPA-4 a + b- (99%), HPA-5 a + b- (76.5%), HPA-6 a + b- (100%) and HPA-15 a + b + (50%). The prevalent allele among the HPA systems was (a), except in the HPA-15 system where the (b) allele was found in 52% of the subjects. (PMID:27019315)
• CD109 knockdown upregulated IL-8 expression through activation of TGF-beta/Akt/NF-kappaB pathway in human umbilical vein endothelial cells (PMID:27121053)
• CD109 is a putative biomarker for identifying a high-risk group among DLBCL patients. (PMID:28032275)
• High expression of CD109 in brain tumor stem cells is involved in glioma progression. (PMID:28888050)
• GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-beta signaling by promoting the routing of the TGF-beta receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. (PMID:29654145)
• CD109 acts as a gatekeeper of the epithelial trait by suppressing epithelial to mesenchymal transition in squamous cell carcinoma cells in vitro. (PMID:31695056)
• CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells. (PMID:32007357)
• Expression of CD109 is correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression is associated with tumor progression, distant metastasis, and poor prognosis in patients. Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF-elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. (PMID:32133706)
• CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma. (PMID:32507856)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	cd109	ENSDARG00000060609
mus_musculus	Cd109	ENSMUSG00000046186
rattus_norvegicus	Cd109	ENSRNOG00000025332
drosophila_melanogaster	Tep4	FBGN0041180
drosophila_melanogaster	Tep3	FBGN0041181
drosophila_melanogaster	Tep2	FBGN0041182
drosophila_melanogaster	Tep1	FBGN0041183
caenorhabditis_elegans	tep-1	WBGENE00013969

Paralogs (8): C5 (ENSG00000106804), C3 (ENSG00000125730), PZP (ENSG00000126838), CPAMD8 (ENSG00000160111), A2ML1 (ENSG00000166535), A2M (ENSG00000175899), C4B (ENSG00000224389), C4A (ENSG00000244731)

Protein

Protein identifiers

CD109 antigen — Q6YHK3 (reviewed: Q6YHK3)

Alternative names: 150 kDa TGF-beta-1-binding protein, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 7, Platelet-specific Gov antigen, p180, r150

All UniProt accessions (1): Q6YHK3

UniProt curated annotations — full annotation on UniProt →

Function. Modulates negatively TGFB1 signaling in keratinocytes.

Subunit / interactions. Heterodimer; disulfide-linked. Interacts with TGFB1 and TGFBR1. Forms a heteromeric complex with TGFBR1, TGFBR2 and TGFBR3 in a ligand-independent manner.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed with high level in uterus, aorta, heart, lung, trachea, placenta and in fetal heart, kidney, liver, spleen and lung. Expressed by CD34(+) acute myeloid leukemia cell lines, T-cell lines, activated T-lymphoblasts, endothelial cells and activated platelets. Isoform 4 is expressed in placenta. Isoform 1 is expressed in keratinocytes and placenta.

Post-translational modifications. N-glycosylated. 2 forms of 150 (p150) and 120 kDa (p120) exist due to proteolytic degradation from a 180 kDa form.

Polymorphism. The Gov(b) variant in position 703 defines the Gov alloantigenic determinants.

Similarity. Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6YHK3-1	1, CD109 180-kDa	yes
Q6YHK3-2	2
Q6YHK3-3	3
Q6YHK3-4	4, CD109S

RefSeq proteins (3): NP_001153059, NP_001153060, NP_598000* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001599	Macroglobln_a2	Domain
IPR002890	MG2	Domain
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR009048	A-macroglobulin_rcpt-bd	Domain
IPR011625	A2M_N_BRD	Domain
IPR011626	Alpha-macroglobulin_TED	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR019742	MacrogloblnA2_CS	Conserved_site
IPR036595	A-macroglobulin_rcpt-bd_sf	Homologous_superfamily
IPR041555	MG3	Domain
IPR041813	A2M_TED	Domain
IPR047565	Alpha-macroglob_thiol-ester_cl	Conserved_site
IPR050473	A2M/Complement_sys	Family

Pfam: PF00207, PF01835, PF07677, PF07678, PF07703, PF17791

UniProt features (37 total): sequence variant 12, glycosylation site 10, sequence conflict 5, splice variant 4, signal peptide 1, chain 1, cross-link 1, propeptide 1, region of interest 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8S3O	ELECTRON MICROSCOPY	2.99
9FX3	ELECTRON MICROSCOPY	3.2
9FX2	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6YHK3-F1	81.42	0.31

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 (2): 921–924, 1420

Glycosylation sites (10): 419, 513, 645, 1086, 1355, 68, 118, 247, 279, 365

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-109582	Hemostasis
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 249 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, WANG_CLIM2_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ZHAN_MULTIPLE_MYELOMA_MF_UP, GOBP_KERATINOCYTE_PROLIFERATION, KOINUMA_COLON_CANCER_MSI_UP

GO Biological Process (9): hair follicle development (GO:0001942), negative regulation of keratinocyte proliferation (GO:0010839), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), keratinocyte proliferation (GO:0043616), regulation of keratinocyte differentiation (GO:0045616), negative regulation of wound healing (GO:0061045), stem cell proliferation (GO:0072089), osteoclast fusion (GO:0072675), negative regulation of stem cell proliferation (GO:2000647)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), endopeptidase inhibitor activity (GO:0004866), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), platelet alpha granule membrane (GO:0031092), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Post-translational protein modification	1
Metabolism of proteins	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
membrane	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
epithelial cell proliferation	1
keratinocyte differentiation	1
regulation of epidermal cell differentiation	1
negative regulation of response to external stimulus	1
wound healing	1
regulation of wound healing	1
negative regulation of response to wounding	1
cell population proliferation	1
stem cell division	1
syncytium formation by cell-cell fusion	1
multinuclear osteoclast differentiation	1
negative regulation of cell population proliferation	1
stem cell proliferation	1
regulation of stem cell proliferation	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cytoplasm	1
cell periphery	1
secretory granule membrane	1
platelet alpha granule	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD109	TGFB1	P01137	884
CD109	CD248	Q9HCU0	613
CD109	FURIN	P09958	607
CD109	CD34	P28906	598
CD109	CD151	P48509	585
CD109	CD44	P16070	582
CD109	CD9	P21926	559
CD109	CD81	P18582	542
CD109	CD63	P08962	529
CD109	CD276	Q5ZPR3	529
CD109	ALPL	P05186	447
CD109	IL10	P22301	445
CD109	ENO2	P09104	435
CD109	PFKP	Q01813	432
CD109	PKM	P14618	423

IntAct

81 interactions, top by confidence:

A	B	Type	Score
CAPN1	CAPNS1	psi-mi:“MI:0914”(association)	0.840
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
SCGB1D1	MANBA	psi-mi:“MI:0914”(association)	0.640
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
IFNA21	IFIT3	psi-mi:“MI:0914”(association)	0.530
SCGB1D4	EGFR	psi-mi:“MI:0914”(association)	0.530
ENPP7	TUBB3	psi-mi:“MI:0914”(association)	0.530
IFNE	FAT1	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
	RAP1BL	psi-mi:“MI:0915”(physical association)	0.400
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Actb		psi-mi:“MI:0914”(association)	0.350
Flnb	RPL22	psi-mi:“MI:0914”(association)	0.350
Calml3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Csnk1d	WWP2	psi-mi:“MI:0914”(association)	0.350
SYNPO	LMO7	psi-mi:“MI:0914”(association)	0.350
MAPRE1	CTNNB1	psi-mi:“MI:0914”(association)	0.350
Myh9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (146): CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CD109 (Affinity Capture-MS)

ESM2 similar proteins: A0AAQ4VMX2, A0RZC6, A8K7I4, C9XI63, C9XI66, I2C090, J3S836, P01023, P01024, P01025, P01026, P01027, P01029, P01030, P01031, P06684, P06756, P08649, P08650, P0C0L4, P0C0L5, P12247, P12387, P19069, P20740, P26007, P26008, P56652, P80746, P97280, P98093, Q01833, Q06033, Q0ZZJ6, Q2UVX4, Q3UU35, Q5RB37, Q61704, Q61739, Q63041

Diamond homologs: P20737, P20738, Q6YHK3, C9XI63, P01023, P06238, P14046, P20740, P20742, P28665, P28666, Q03626, Q5R4N8, Q61838, Q63041, Q6GQT1, Q6IE52, Q7SIH1, Q8IZJ3, Q8R422, Q9GYW4, A8K2U0, P20739, Q3UU35, C9XI66, P30800, Q6IE37, Q6ZMU1, J3S836, P01024, P01025, P01026, P01027, P06684, P08650, P0C0L4, P0C0L5, P12247, P12387, Q2UVX4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	217
Likely benign	14
Benign	13

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1340605	GRCh37/hg19 6q13-14.1(chr6:70165296-79920769)x1	Pathogenic
980211	GRCh37/hg19 6q13-14.1(chr6:74226559-80208037)x1	Pathogenic

SpliceAI

6374 predictions. Top by Δscore:

Variant	Effect	Δscore
6:73697569:AAAGG:A	donor_loss	1.0000
6:73697571:AG:A	donor_gain	1.0000
6:73697572:GG:G	donor_gain	1.0000
6:73697573:GTAAG:G	donor_loss	1.0000
6:73697574:T:A	donor_loss	1.0000
6:73723277:TCA:T	donor_gain	1.0000
6:73723280:G:GG	donor_gain	1.0000
6:73724325:A:T	donor_gain	1.0000
6:73730500:G:GT	donor_gain	1.0000
6:73730505:G:GT	donor_gain	1.0000
6:73736505:GAAT:G	donor_gain	1.0000
6:73736509:G:GG	donor_gain	1.0000
6:73758942:A:AG	acceptor_gain	1.0000
6:73758943:G:GG	acceptor_gain	1.0000
6:73758943:GT:G	acceptor_gain	1.0000
6:73758943:GTATT:G	acceptor_gain	1.0000
6:73759029:G:GG	donor_gain	1.0000
6:73762768:A:AG	acceptor_gain	1.0000
6:73762878:TACAG:T	donor_loss	1.0000
6:73762879:ACAG:A	donor_loss	1.0000
6:73762883:G:A	donor_loss	1.0000
6:73762884:T:G	donor_loss	1.0000
6:73766059:G:GT	donor_gain	1.0000
6:73766138:G:GG	donor_gain	1.0000
6:73766202:GTT:G	donor_gain	1.0000
6:73766996:GAGT:G	donor_gain	1.0000
6:73766999:T:G	donor_gain	1.0000
6:73771424:TTTA:T	acceptor_loss	1.0000
6:73771427:A:AC	acceptor_loss	1.0000
6:73771427:A:AG	acceptor_gain	1.0000

AlphaMissense

9497 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:73730513:G:C	R149P	0.999
6:73736485:T:A	W204R	0.996
6:73736485:T:C	W204R	0.996
6:73782730:T:A	W694R	0.994
6:73782730:T:C	W694R	0.994
6:73758955:T:C	F229L	0.990
6:73758957:T:A	F229L	0.990
6:73758957:T:G	F229L	0.990
6:73759024:G:C	A252P	0.990
6:73783759:T:A	W720R	0.990
6:73783759:T:C	W720R	0.990
6:73759025:C:A	A252E	0.988
6:73768130:T:A	W525R	0.988
6:73768130:T:C	W525R	0.988
6:73771481:T:C	L576P	0.988
6:73803235:T:C	L965P	0.987
6:73766144:T:C	L441P	0.986
6:73762422:T:C	L266P	0.984
6:73803270:T:C	F977L	0.984
6:73803272:T:A	F977L	0.984
6:73803272:T:G	F977L	0.984
6:73730378:T:C	L104P	0.983
6:73803264:A:C	S975R	0.983
6:73803266:T:A	S975R	0.983
6:73803266:T:G	S975R	0.983
6:73782736:T:A	W696R	0.982
6:73782736:T:C	W696R	0.982
6:73803261:T:C	F974L	0.981
6:73803263:C:A	F974L	0.981
6:73803263:C:G	F974L	0.981

dbSNP variants (sampled 300 via entrez): RS1000008653 (6:73821709 TG>T), RS1000020487 (6:73681843 T>G), RS1000035426 (6:73732490 AC>A,ACC), RS1000055856 (6:73688776 T>G), RS1000060875 (6:73740743 C>A,T), RS1000089718 (6:73712386 G>T), RS1000098263 (6:73770272 A>C,G), RS1000136061 (6:73715323 G>A), RS1000144865 (6:73785282 T>A), RS1000204188 (6:73704359 C>A,T), RS1000214913 (6:73766534 T>C), RS1000255429 (6:73732127 T>G), RS1000278187 (6:73805824 T>G), RS1000310595 (6:73693593 C>G,T), RS1000315145 (6:73760173 C>T)

Disease associations

OMIM: gene MIM:608859 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): multiple sclerosis (MONDO:0005301)

Orphanet (1): NON RARE IN EUROPE: Multiple sclerosis (Orphanet:802)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000618	Blindness
HP:0000707	Abnormality of the nervous system
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000979	Purpura
HP:0001263	Global developmental delay
HP:0001892	Abnormal bleeding
HP:0002138	Subarachnoid hemorrhage
HP:0002170	Intracranial hemorrhage
HP:0002239	Gastrointestinal hemorrhage
HP:0002249	Melena
HP:0004809	Neonatal alloimmune thrombocytopenia
HP:0007420	Spontaneous hematomas
HP:0008619	Bilateral sensorineural hearing impairment
HP:0012541	Cephalohematoma
HP:0031364	Ecchymosis
HP:0100021	Cerebral palsy

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001762_188	Obesity-related traits	9.000000e-06
GCST002201_9	Calcium levels	3.000000e-06
GCST002936_18	Cadmium levels	1.000000e-10
GCST006288_456	Heel bone mineral density	1.000000e-06
GCST006288_552	Heel bone mineral density	1.000000e-12
GCST006585_1272	Blood protein levels	1.000000e-115
GCST006979_296	Heel bone mineral density	1.000000e-37
GCST009391_1738	Metabolite levels	2.000000e-06
GCST010867_64	Coronary artery disease	4.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004838	calcium measurement
EFO:0009270	heel bone mineral density
EFO:0010376	phosphatidylcholine 34:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009103	Multiple Sclerosis	C10.114.375.500; C10.314.350.500; C20.111.258.250.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	8
Tetrachlorodibenzodioxin	increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Valproic Acid	affects cotreatment, increases expression, decreases expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Dinitrochlorobenzene	affects binding, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	increases expression	1
arsenite	affects expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	increases expression	1
nickel chloride	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
coumarin	increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dimethylarsinous acid	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2TB	HP-15a	Cancer cell line	Female
CVCL_E2TC	HP-15b	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00037102	PHASE4	COMPLETED	Combination Therapy With Avonex and BiMonthly High Dose Intravenous Methotrexate in Multiple Sclerosis
NCT00037115	PHASE4	WITHDRAWN	Induction Therapy With a Single High Dose Bolus of Intravenous Methotrexate With Leucovorin Rescue, Prior to Initiation of AVONEX® Treatment, in Patients Presenting With a First Acute Demyelinating Event.
NCT00146068	PHASE4	COMPLETED	EARLY IFNB-1a and Simvastatin Combination Therapy in Clinically Isolated Syndrome Suggestive of Multiple Sclerosis
NCT00151294	PHASE4	TERMINATED	The Efficacy and Safety of Escitalopram for Depression in Multiple Sclerosis
NCT00176592	PHASE4	COMPLETED	Phase IV Study, Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI
NCT00179478	PHASE4	COMPLETED	Long Term Study of Avonex Therapy Following a First Attack of Multiple Sclerosis
NCT00220922	PHASE4	COMPLETED	A Study to Evaluate the Impact on Skin (Injection Site) Reactions of Using Alcohol Wipes Prior to Daily Injections of Copaxone®.
NCT00239993	PHASE4	COMPLETED	A Study to Evaluate the Impact of Using Warm Compress Prior to Daily Injections of Copaxone®
NCT00240006	PHASE4	COMPLETED	A Study Comparing Shared Solutions® Plus MS Center Support Versus Shared Solutions® Alone
NCT00240032	PHASE4	COMPLETED	A Study to Evaluate the Impact on Skin (Injection Site) Reactions of Taking an Antihistamine (Zyrtec®) or Placebo Prior to Daily Injections of Copaxone®.
NCT00246324	PHASE4	COMPLETED	Safety and Efficacy Study of Doxycycline in Combination With Interferon-B-1a to Treat Multiple Sclerosis
NCT00267319	PHASE4	COMPLETED	FOCUS Fatigue Outcome in Copaxone USers
NCT00381264	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Multiple Sclerosis
NCT00414453	PHASE4	TERMINATED	Trial of Analgesia With Lidocaine or Extended-release Oxycodone for Neuropathic Pain Treatment in Multiple Sclerosis
NCT00423527	PHASE4	COMPLETED	Levetiracetam in Central Pain in Multiple Sclerosis(MS)
NCT00480181	PHASE4	COMPLETED	Efficacy and Safety Evaluation of Nabilone as Adjunctive Therapy to Gabapentin for the Management of Neuropathic Pain in Multiple Sclerosis
NCT00492765	PHASE4	COMPLETED	Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis
NCT00493077	PHASE4	COMPLETED	Safety of Avonex Treatment in Multiple Sclerosis Patients With Neutralizing Antibodies to Interferon Beta Therapy
NCT00536120	PHASE4	COMPLETED	The Effects of Tysabri Treatment on Vaccination Response and Lymphocyte Subsets in Subjects With Relapsing Forms of Multiple Sclerosis
NCT00629642	PHASE4	COMPLETED	Clinical Study of Solifenacin Succinate in Patients With Bladder Symptoms Due to Spinal Cord Injury or Multiple Sclerosis
NCT00638027	PHASE4	COMPLETED	Memantine for Spasticity in MS Patients
NCT00744679	PHASE4	COMPLETED	A Pharmacokinetic (PK) Study of Natalizumab (Tysabri) at Steady State
NCT00752778	PHASE4	TERMINATED	Magnetic Resonance Imaging (MRI) Follow-up of Macrophagic Infiltration in MS Patients Treated With Tysabri
NCT00753792	PHASE4	COMPLETED	Oral Corticotherapy in Megadoses to Treat Multiple Sclerosis During Relapse
NCT00854750	PHASE4	TERMINATED	Modeling and Treating the Pathophysiology of Demyelination in Multiple Sclerosis
NCT00881205	PHASE4	TERMINATED	Rivastigmine in Multiple Sclerosis Patients With Cognitive Impairment
NCT00910598	PHASE4	UNKNOWN	Optical Coherence Tomography: Glatiramer in Clinically Isolated Syndrome or Early Relapsing Remitting Multiple Sclerosis (MS)
NCT00913666	PHASE4	COMPLETED	Pharmacodynamic Study to Better Understand the Therapeutic Response and Immunomodulatory Effects of Avonex in Multiple Sclerosis (MS) Patients and Healthy Volunteers
NCT00915460	PHASE4	COMPLETED	Open-Label Safety Extension Study of Avonex
NCT00942214	PHASE4	COMPLETED	Biomarkers and Response to Natalizumab for Multiple Sclerosis Treatment
NCT00988988	PHASE4	WITHDRAWN	The Effects of Ethyl-Alpha-Guanido-Methyl Ethanoate on Skin Reactions From Glatiramer Acetate Injections
NCT01005095	PHASE4	TERMINATED	The Effects of Interferon Beta Combined With Vitamin D on Relapsing Remitting Multiple Sclerosis Patients
NCT01034579	PHASE4	COMPLETED	The REbif® vs Glatiramer Acetate in Relapsing Multiple Sclerosis Pharmacogenetics Trial
NCT01085318	PHASE4	COMPLETED	Rebif Advanced Magnetic Resonance Imaging (MRI) and Immunology Pilot Trial
NCT01236534	PHASE4	COMPLETED	Lubiprostone in Patients With Multiple Sclerosis Associated Constipation
NCT01333501	PHASE4	COMPLETED	Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms
NCT01339676	PHASE4	UNKNOWN	Colecalciferol as an Add-on Treatment to Interferon-beta-1b for Treatment of Multiple Sclerosis (MS)
NCT01356940	PHASE4	COMPLETED	A Placebo Controlled Trial of Dalfampridine ER for Ambulatory Activity in People With Multiple Sclerosis
NCT01395316	PHASE4	COMPLETED	Alemtuzumab on Surrogate Markers of Disease Activity and Repair Using Advanced MRI Measures in Subjects With Relapsing Remitting Multiple Sclerosis
NCT01411514	PHASE4	TERMINATED	Oral Prednisone Taper Versus Placebo for the Treatment of Acute Relapses in Multiple Sclerosis