CD9

Summary

CD9 (CD9 molecule, HGNC:1709) is a protein-coding gene on chromosome 12p13.31, encoding CD9 antigen (P21926). Integral membrane protein associated with integrins, which regulates different processes, such as sperm-egg fusion, platelet activation and aggregation, and cell adhesion.

This gene encodes a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Tetraspanins are cell surface glycoproteins with four transmembrane domains that form multimeric complexes with other cell surface proteins. The encoded protein functions in many cellular processes including differentiation, adhesion, and signal transduction, and expression of this gene plays a critical role in the suppression of cancer cell motility and metastasis.

Source: NCBI Gene 928 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 24 total
• GTEx eGene: eQTL in 13 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.93 (loss-of-function intolerant), LOEUF 0.56 (moderately constrained)
• MANE Select transcript: NM_001769
• Interaction hub: 2,944 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1709
Approved symbol	CD9
Name	CD9 molecule
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	BA2, P24, TSPAN29, MRP-1
Ensembl gene	ENSG00000010278
Ensembl biotype	protein_coding
OMIM	143030
Entrez	928

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 22 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000009180

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 2, TSL 5: 5

ENST00000009180, ENST00000382515, ENST00000382518, ENST00000382519, ENST00000481267, ENST00000536586, ENST00000538418, ENST00000538834, ENST00000540891, ENST00000543916, ENST00000546073, ENST00000610354, ENST00000642746, ENST00000645368, ENST00000645565, ENST00000646407, ENST00000676638, ENST00000676764, ENST00000676788, ENST00000677318, ENST00000677572, ENST00000677585, ENST00000677718, ENST00000678719, ENST00000679331, ENST00000894339, ENST00000894340, ENST00000894341, ENST00000924981, ENST00000924982, ENST00000924983, ENST00000924984, ENST00000947407, ENST00001010389, ENST00001084487, ENST00001084492, ENST00001084502, ENST00001124095

RefSeq mRNA: 14 — MANE Select: NM_001769 NM_001330312, NM_001413241, NM_001413242, NM_001413243, NM_001413244, NM_001413245, NM_001413246, NM_001413247, NM_001413248, NM_001413249, NM_001413250, NM_001413251, NM_001413252, NM_001769

CCDS: CCDS81654, CCDS8540

Canonical transcript exons

ENST00000009180 — 8 exons

Exon	Start	End
ENSE00001832813	6200400	6200565
ENSE00003501746	6236192	6236275
ENSE00003610238	6232632	6232729
ENSE00003635630	6233412	6233486
ENSE00003646744	6235476	6235565
ENSE00003653329	6235229	6235327
ENSE00003668112	6225426	6225534
ENSE00003848695	6237763	6238266

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 223.2810 / max 2919.6321, expressed in 1728 samples.

Highest expression (Bgee): pharyngeal mucosa, seminal vesicle, mucosa of sigmoid colon, colonic mucosa, trigeminal ganglion.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD9 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.3e-37	-0.55	12:6136532:A:G
Spleen	sqtl	2.8e-20	-0.88	12:6183258:GCT:G
Esophagus Mucosa	eqtl	4.3e-15	-0.24	12:6065248:T:G
Cells Cultured fibroblasts	eqtl	1.1e-12	+0.32	12:6293021:A:G
Testis	eqtl	3.7e-10	+0.26	12:6274359:G:C
Brain Cerebellum	eqtl	8.9e-06	+0.28	12:6236033:C:T
Nerve Tibial	eqtl	9.3e-06	+0.12	12:6254134:A:G
Cells EBV-transformed lymphocytes	eqtl	1.6e-05	+0.31	12:6182499:CG:C
Liver	eqtl	2.0e-05	-0.31	12:6182499:CG:C
Liver	sqtl	4.2e-05	-0.50	12:6182499:CG:C
Colon Transverse	eqtl	6.0e-04	+0.35	12:6218083:T:C
Thyroid	eqtl	1.2e-03	+0.11	12:6204245:A:G
Pancreas	eqtl	1.5e-03	+0.19	12:6200729:G:A
Brain Cerebellar Hemisphere	eqtl	8.7e-03	+0.18	12:6230690:T:C
Adipose Visceral Omentum	eqtl	1.7e-02	+0.16	12:6196022:C:A
Adrenal Gland	sqtl	3.8e-02	+0.37	12:6216416:C:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
123626	213.6073	1724
123625	8.8651	1610
123624	0.4838	253
123627	0.2047	71
123623	0.1069	27
123628	0.0133	4

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	99.83	gold quality
seminal vesicle	UBERON:0000998	99.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.78	gold quality
colonic mucosa	UBERON:0000317	99.74	gold quality
trigeminal ganglion	UBERON:0001675	99.73	gold quality
calcaneal tendon	UBERON:0003701	99.73	gold quality
esophagus squamous epithelium	UBERON:0006920	99.73	gold quality
urethra	UBERON:0000057	99.72	gold quality
synovial joint	UBERON:0002217	99.72	gold quality
bronchial epithelial cell	CL:0002328	99.70	gold quality
oral cavity	UBERON:0000167	99.69	gold quality
epithelium of esophagus	UBERON:0001976	99.69	gold quality
nasal cavity mucosa	UBERON:0001826	99.68	gold quality
nasal cavity epithelium	UBERON:0005384	99.64	gold quality
palpebral conjunctiva	UBERON:0001812	99.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.61	gold quality
gingiva	UBERON:0001828	99.60	gold quality
penis	UBERON:0000989	99.59	gold quality
epithelium of bronchus	UBERON:0002031	99.59	gold quality
bronchus	UBERON:0002185	99.59	gold quality
esophagus mucosa	UBERON:0002469	99.58	gold quality
trachea	UBERON:0003126	99.58	gold quality
gingival epithelium	UBERON:0001949	99.55	gold quality
upper arm skin	UBERON:0004263	99.55	gold quality
mucosa of transverse colon	UBERON:0004991	99.55	gold quality
mouth mucosa	UBERON:0003729	99.53	gold quality
mucosa of stomach	UBERON:0001199	99.52	gold quality
cartilage tissue	UBERON:0002418	99.52	gold quality
lower lobe of lung	UBERON:0008949	99.52	gold quality
minor salivary gland	UBERON:0001830	99.51	gold quality
rectum	UBERON:0001052	99.49	gold quality
dorsal root ganglion	UBERON:0000044	99.47	gold quality
mammalian vulva	UBERON:0000997	99.46	gold quality
transverse colon	UBERON:0001157	99.46	gold quality
upper leg skin	UBERON:0004262	99.46	gold quality
esophagus	UBERON:0001043	99.45	gold quality
olfactory bulb	UBERON:0002264	99.45	gold quality
periodontal ligament	UBERON:0008266	99.45	gold quality
saliva-secreting gland	UBERON:0001044	99.44	gold quality
sigmoid colon	UBERON:0001159	99.44	gold quality
tibial nerve	UBERON:0001323	99.42	gold quality
skin of hip	UBERON:0001554	99.41	gold quality
skin of abdomen	UBERON:0001416	99.40	gold quality
nipple	UBERON:0002030	99.40	gold quality
vagina	UBERON:0000996	99.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.37	gold quality
lower esophagus mucosa	UBERON:0035834	99.37	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.37	gold quality
large intestine	UBERON:0000059	99.36	gold quality
left lobe of thyroid gland	UBERON:0001120	99.35	gold quality
colon	UBERON:0001155	99.35	gold quality
tongue squamous epithelium	UBERON:0006919	99.35	gold quality
body of tongue	UBERON:0011876	99.35	gold quality
zone of skin	UBERON:0000014	99.34	gold quality
tendon of biceps brachii	UBERON:0008188	99.34	gold quality
skin of leg	UBERON:0001511	99.31	gold quality
descending thoracic aorta	UBERON:0002345	99.31	gold quality
ascending aorta	UBERON:0001496	99.30	gold quality
metanephros cortex	UBERON:0010533	99.30	gold quality
thoracic aorta	UBERON:0001515	99.29	gold quality
lower esophagus	UBERON:0013473	99.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.29	gold quality
aorta	UBERON:0000947	99.26	gold quality
renal medulla	UBERON:0000362	99.25	gold quality
right lobe of thyroid gland	UBERON:0001119	99.23	gold quality
right lung	UBERON:0002167	99.23	gold quality
popliteal artery	UBERON:0002250	99.23	gold quality
tonsil	UBERON:0002372	99.23	gold quality
tibial artery	UBERON:0007610	99.23	gold quality
thyroid gland	UBERON:0002046	99.22	gold quality
pericardium	UBERON:0002407	99.22	gold quality
tongue	UBERON:0001723	99.21	gold quality
prostate gland	UBERON:0002367	99.20	gold quality
vena cava	UBERON:0004087	99.20	gold quality
right coronary artery	UBERON:0001625	99.19	gold quality
tendon	UBERON:0000043	99.18	gold quality
saphenous vein	UBERON:0007318	99.16	gold quality
left coronary artery	UBERON:0001626	99.15	gold quality
ectocervix	UBERON:0012249	99.13	gold quality
endocervix	UBERON:0000458	99.12	gold quality
urinary bladder	UBERON:0001255	99.12	gold quality
upper lobe of lung	UBERON:0008948	99.11	gold quality
left adrenal gland cortex	UBERON:0035825	99.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.09	gold quality
left adrenal gland	UBERON:0001234	99.08	gold quality
corpus callosum	UBERON:0002336	99.08	gold quality
upper lobe of left lung	UBERON:0008952	99.08	gold quality
spinal cord	UBERON:0002240	99.07	gold quality
mucosa of urinary bladder	UBERON:0001259	99.06	gold quality
caput epididymis	UBERON:0004358	99.05	gold quality
germinal epithelium of ovary	UBERON:0001304	99.04	gold quality
intestine	UBERON:0000160	99.03	gold quality
adrenal cortex	UBERON:0001235	99.03	gold quality
epithelium of nasopharynx	UBERON:0001951	99.03	gold quality
corpus epididymis	UBERON:0004359	99.03	gold quality
layer of synovial tissue	UBERON:0007616	98.99	gold quality
coronary artery	UBERON:0001621	98.98	gold quality
adult organism	UBERON:0007023	98.97	gold quality
body of uterus	UBERON:0009853	98.97	gold quality
superior surface of tongue	UBERON:0007371	98.96	gold quality

Single-cell (SCXA)

Detected in 44 experiment(s), a significant marker in 39.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	12004.01
E-HCAD-11	yes	5163.27
E-MTAB-8410	yes	4889.04
E-CURD-46	yes	4450.07
E-MTAB-8322	yes	3494.48
E-CURD-114	yes	2142.87
E-MTAB-9067	yes	2026.19
E-HCAD-1	yes	1826.33
E-HCAD-6	yes	1495.79
E-MTAB-8221	yes	1286.21
E-HCAD-9	yes	1197.66
E-GEOD-137537	yes	985.93
E-MTAB-11121	yes	823.48
E-HCAD-4	yes	77.46
E-CURD-122	yes	67.11

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Parathyroid gland	tissue	828.3	high
Esophagus	tissue	753.9	medium
Salivary gland	tissue	527.8	high
Vagina	tissue	459.8	high
Prostate	tissue	458.5	high
Rectum	tissue	437.7	high
Seminal vesicle	tissue	430.1	high
Colon	tissue	425.3	high
Lung	tissue	379.8	high
Corpus callosum	tissue	375.5
Urinary bladder	tissue	348.5	high
Skin 1	tissue	335.9	high
Cervix	tissue	303.1	high
Spinal cord	tissue	299.2
Thyroid gland	tissue	285.8	medium
Breast	tissue	280.2	not detected
Tonsil	tissue	271.2	low
Epididymis	tissue	255.9	medium
Adrenal gland	tissue	231.4	medium
Fallopian tube	tissue	227.9	high
Kidney	tissue	223.1	high
Medulla oblongata	tissue	205.7
Substantia nigra	tissue	201.7
Midbrain	tissue	195.7
Smooth muscle	tissue	183.9	medium
Choroid plexus	tissue	170.5
Endometrium 1	tissue	164.1	medium
Periaqueductal gray	tissue	162.3
Small intestine	tissue	162.0	high
Thalamus	tissue	152.4
Superior colliculi	tissue	151.4
Caudate putamen	tissue	142.7
Pons	tissue	133.7
Hypothalamus	tissue	121.9
Heart muscle	tissue	120.3	not detected
Putamen	tissue	120.0
Duodenum	tissue	119.7	low
Hippocampal formation	tissue	118.4
Ventral forebrain	tissue	112.4
Tongue	tissue	108.7
Stomach 1	tissue	98.7	medium
Gallbladder	tissue	96.0	not detected
Septum	tissue	95.3
Nucleus accumbens	tissue	93.7
Frontal cortex	tissue	91.5
Appendix	tissue	91.1	medium
Pancreas	tissue	85.5	medium
Hippocampus	tissue	84.5	low
Olfactory bulb	tissue	80.9
Placenta	tissue	80.2	not detected
Pituitary gland	tissue	78.2
Amygdala	tissue	75.9
Adipose tissue	tissue	74.3	not detected
Liver	tissue	74.1	not detected
Locus coeruleus	tissue	67.4
Cerebral cortex	tissue	63.2	medium
Retrosplenial cortex	tissue	63.2
Thymus	tissue	61.6
Spleen	tissue	59.2	medium
Somatosensory cortex	tissue	58.3

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (399.0), White matter (375.5), Dorsal spinal cord (299.2), Ventral spinal cord (287.6), Corpus callosum, splenium (white matter) (266.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, EGR1, FOSB, JUN, PITX2, SP1, STAT3

Functional genomics

gnomAD constraint: pLI 0.932, LOEUF 0.555, missense Z 0.423 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000009180 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 40)

• peripheral blood monocytes treated for 5–8 days with GM-CSF (i.e. mature Mphi) acquired the capacity to assemble CD9 with alpha3-beta1 integrin, tyrosine phosphatase SHP-1 and with CD46. (PMID:11858824)
• CD9 protein expression was inversely associated with lymph node metastasis. (PMID:11920609)
• By site-directed mutagenesis, CD9 was found to be palmitoylated at any of the four internal juxtamembrane regions. (PMID:11959120)
• C-kit is physically associated with transmembrane 4 superfamily proteins CD9, CD63, and CD81, that may negatively modulate c-kit and thus regulate c-kit receptor sensitivity to SLF in hematopoietic progenitors. (PMID:12036870)
• Infertility of CD9-deficient mouse eggs is reversed by human CD9 (PMID:12086470)
• Data show that the expression of the PAINS-13 epitope depends on CD9 association with alpha(6)beta(1) integrin. (PMID:12411441)
• The second extracellular loop sequence (173)LETFTVKSCPDAIKEVFDNK(192) is largely responsible for trasnfected human CD9-mediated CHO cell adhesion to fibronectin and fibronectin pericellular matrix assembly. (PMID:12453879)
• low expression of CD9 may contribute to the highly invasive and metastatic phenotype of small cell lung cancer (PMID:12569360)
• downregulation of CD9 antigen is associated with breast tumor progression (PMID:12579280)
• CD9 expression was rather intensified in gastric cancer tissue in comparison with normal tissues. CD9 expression was more prominent in advanced gastric cancer. (PMID:15047125)
• CD9 does not have a role in progression of human osteosarcoma or predict its prognosis (PMID:15145525)
• CD9 activates the p46 Shc isoform in tumor cells and leads to apoptosis (PMID:15226408)
• cell-surface expression of CD9, a beta1 integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleotide-treated cells. (PMID:15389525)
• The MRP-1/CD9 gene expression was down-regulated in gastric cancer, its expression was probably related to the carcinogenesis and histology types of gastric cancer. (PMID:15476162)
• endothelial CD9 tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (PMID:15591117)
• leukocyte antigen-DR, CD38, and CD9 share a common pathway of tyrosine kinase activation in human monocytes (PMID:15941914)
• tetraspanin intra- and intermolecular interactions are mediated by conserved residues in adjacent, but distinct regions of TM1 and TM2 (PMID:15985154)
• phenotypic conversion and reversion of bladder cancer cells is controlled by a glycosynapse 3 microdomain through GM3-mediated interaction of alpha3beta1 integrin with CD9 (PMID:16103120)
• results have shown that CD-9 is present in prostate tumour epithelial cells and that it is regulated by androgens in LNCaP-FGC cells (PMID:16128989)
• CD9 is essential for the IL-16-mediated chemotaxis and activation, acting as an IL-16 receptor in HMC-1, a mast cell line that lacks CD4 (PMID:16144798)
• A role of CD9 in melanocyte motility was shown. (PMID:16297202)
• results suggest that the restored expression of CD9 in SCLC cells may reduce the metastatic spread of SCLC cells via the inhibition of cell proliferation and motility (PMID:16491954)
• EWI proteins EWI-2 and EWI-F, alpha3beta1 and alpha6beta4 integrins, and protein palmitoylation have contrasting effects on cell surface CD9 organization (PMID:16537545)
• MRP-1/CD9 regulates the actin cytoskeleton by downregulating of the WAVE2, through the Wnt-independent signal pathway. (PMID:16682943)
• CD9 expression by multiple myeloma cells is upregulated in vivo by close interaction of the cells with endothelial cells and CD9 is involved in transendothelial invasion (PMID:16900214)
• CD9 molecules on endothelial cells participate in the mitogenic effect of platelets; results suggest that the tetraspanin CD9 plays an important role in endothelial regeneration (PMID:16951553)
• role of CD81 and CD9 on the cell-to-cell fusion process mediated by HIV-1, syncytia formation induced by HIV-1 envelope proteins and viral entry in human T lymphoblasts (PMID:17015697)
• Ectopic CD9 expression suppressed neurite-like process outgrowth & promoted apoptotic death of some SCLC cells. Its absence in SLCL may contribute to postadhesive morphologic differentiation, survival, & MMP-2 production via PI3K/Akt pathway. (PMID:17018612)
• results clearly point to an involvement of CD9 in the attachment, uptake or processing of adeno-associated virus-2 by target cells (PMID:17203208)
• Expression of CD9 in transitional cell carcinoma bladder is reported. (PMID:17393117)
• CD9 gene inactivation may play an important role in prostate cancer progression. (PMID:17406028)
• transferrin receptor and CD9, CD81, and CD9P-1 are differentially sorted into exosomes after TPA treatment of K562 cells (PMID:17407154)
• Data show that HIV-1 envelope glycoprotein (Env) and core protein (Gag) colocalize strongly with CD63 and CD81 and less strongly with CD9, and suggest that HIV-1 promotes virus assembly and cell-cell transfer by targeting these plasma membrane proteins. (PMID:17522207)
• establish for the first time a role for CD9 in the tumorigenic process (PMID:17582603)
• Nine potential tetraspanin CD9 partners, including claudin-1, were identified. (PMID:17644758)
• CD9 plays roles in cell proliferation and attachment in vitro as well as in in vivo engraftment and that it can be considered as a useful marker to predict the in vivo efficacy of human adipose-derived mesenchymal stem cells. (PMID:17668233)
• CD10 and CD9 expression correlates with the invasiveness and metastatic potential of malignant melanoma. (PMID:17845760)
• The absence or down-regulation of CD9 expression and point mutation may play a considerable role in the pathway of the malignant transformation in the BEAS-2B cells induced by mineral powder. (PMID:17997888)
• examined whether CD63-PI4K55 and CD9-PI4K55 complexes were resident in platelet-lipid rafts, or formed distinct microdomains (PMID:18000614)
• Results demonstrate the physical and functional association of CD9 with epidermal growth factor receptor on MKN-28 cells. (PMID:18247373)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd9	ENSMUSG00000030342
rattus_norvegicus	Cd9	ENSRNOG00000019556

Paralogs (32): TSPAN6 (ENSG00000000003), TSPAN9 (ENSG00000011105), TSPAN17 (ENSG00000048140), TSPAN32 (ENSG00000064201), CD82 (ENSG00000085117), TSPAN15 (ENSG00000099282), CD37 (ENSG00000104894), UPK1A (ENSG00000105668), TSPAN12 (ENSG00000106025), TSPAN13 (ENSG00000106537), TSPAN14 (ENSG00000108219), CD81 (ENSG00000110651), TSPAN11 (ENSG00000110900), PRPH2 (ENSG00000112619), UPK1B (ENSG00000114638), TSPAN1 (ENSG00000117472), TSPAN8 (ENSG00000127324), TSPAN16 (ENSG00000130167), TSPAN2 (ENSG00000134198), CD63 (ENSG00000135404), TSPAN31 (ENSG00000135452), TSPAN3 (ENSG00000140391), CD53 (ENSG00000143119), ROM1 (ENSG00000149489), TSPAN7 (ENSG00000156298), TSPAN18 (ENSG00000157570), TSPAN33 (ENSG00000158457), TSPAN5 (ENSG00000168785), CD151 (ENSG00000177697), TSPAN10 (ENSG00000182612), TSPAN4 (ENSG00000214063), TSPAN19 (ENSG00000231738)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88348) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired fertilization	2
female infertility	2
abnormal oocyte morphology	1
reduced female fertility	1
decreased litter size	1
abnormal definitive hematopoiesis	1
delayed female fertility	1

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Pan troglodytes	P60034	100.0%	Diamond
Chlorocebus aethiops	P61170	100.0%	Diamond
Macaca mulatta	P61171	100.0%	Diamond
Pongo abelii	Q5R8B5	100.0%	Diamond
Bos taurus	Q29RH7	98.0%	Diamond
Saguinus oedipus	Q9N0J9	97.9%	Diamond
Gallus gallus	Q5ZIF5	93.8%	Diamond
Felis catus	P40239	91.2%	Diamond
Sus scrofa	Q8WMQ3	89.5%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
VWF	protein-coding	7450
PLEKHG6	protein-coding	55200
TNFRSF1A	protein-coding	7132
SNORA120	snoRNA	109729112

Protein

Protein identifiers

CD9 antigen — P21926 (reviewed: P21926)

Alternative names: 5H9 antigen, Cell growth-inhibiting gene 2 protein, Leukocyte antigen MIC3, Motility-related protein, Tetraspanin-29, p24

All UniProt accessions (8): P21926, A0A087WU13, A0A2R8Y478, A0A7I2V3T0, A0A7I2V3T7, A6NNI4, F5GXT1, G8JLH6

UniProt curated annotations — full annotation on UniProt →

Function. Integral membrane protein associated with integrins, which regulates different processes, such as sperm-egg fusion, platelet activation and aggregation, and cell adhesion. Present at the cell surface of oocytes and plays a key role in sperm-egg fusion, possibly by organizing multiprotein complexes and the morphology of the membrane required for the fusion. In myoblasts, associates with CD81 and PTGFRN and inhibits myotube fusion during muscle regeneration. In macrophages, associates with CD81 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles. Also prevents the fusion between mononuclear cell progenitors into osteoclasts in charge of bone resorption. Acts as a receptor for PSG17. Involved in platelet activation and aggregation. Regulates paranodal junction formation. Involved in cell adhesion, cell motility and tumor metastasis.

Subunit / interactions. Forms both disulfide-linked homodimers and higher homooligomers as well as heterooligomers with other members of the tetraspanin family. Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3. Interacts with integrin ITGA6:ITGB1; interaction takes place in oocytes and is involved in sperm-egg fusion. Part of integrin-tetraspanin complexes composed of CD81, beta-1 and beta-2 integrins in the membrane of monocyte/macrophages. Interacts with CD63; identified in a complex with CD63 and ITGB3. Associates with CR2/CD21 and with PTGFRN/CD9P1. Part of a complex composed of CD9, CD81, PTGFRN and IGSF8. Interacts directly with IGSF8. Interacts with PDPN; this interaction is homophilic and attenuates platelet aggregation and pulmonary metastasis induced by PDPN. Interacts (on T cell side) with CD81 at immunological synapses between antigen-presenting cells and T cells.

Subcellular location. Cell membrane. Membrane. Secreted. Extracellular exosome.

Tissue specificity. Detected in platelets (at protein level). Expressed by a variety of hematopoietic and epithelial cells.

Post-translational modifications. Palmitoylated at a low, basal level in unstimulated platelets. The level of palmitoylation increases when platelets are activated by thrombin (in vitro). The protein exists in three forms with molecular masses between 22 and 27 kDa, and is known to carry covalently linked fatty acids. Palmitoylation by ZDHHC2 regulates CD9 expression, association with other tetraspanin family proteins and function in cell adhesion.

Similarity. Belongs to the tetraspanin (TM4SF) family.

RefSeq proteins (14): NP_001317241, NP_001400170, NP_001400171, NP_001400172, NP_001400173, NP_001400174, NP_001400175, NP_001400176, NP_001400177, NP_001400178, NP_001400179, NP_001400180, NP_001400181, NP_001760* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000301	Tetraspanin_animals	Family
IPR008952	Tetraspanin_EC2_sf	Homologous_superfamily
IPR018499	Tetraspanin/Peripherin	Family
IPR018503	Tetraspanin_CS	Conserved_site
IPR042055	CD9_LEL	Domain

Pfam: PF00335

UniProt features (40 total): helix 10, lipid moiety-binding region 6, mutagenesis site 6, topological domain 5, transmembrane region 4, glycosylation site 2, disulfide bond 2, turn 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
6Z1V	Structure of the EC2 domain of CD9 in complex with nanobody 4E8	X-RAY DIFFRACTION	1.33
6RLR	Crystal structure of CD9 large extracellular loop	X-RAY DIFFRACTION	2
6RLO	Crystal structure of AT1412dm Fab fragment in complex with CD9 large extracellular loop	X-RAY DIFFRACTION	2.2
6Z20	Structure of the EC2 domain of CD9 in complex with nanobody 4C8	X-RAY DIFFRACTION	2.68
6K4J	Crystal Structure of the the CD9	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21926-F1	88.38	0.61

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 6RLO, 6Z1V, 6Z20

Human Protein Atlas

Protein class: CD markers, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IH supported · IF supported

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 (6)

Type	Positions
S-palmitoyl cysteine	9, 78, 79, 87, 218, 219

Disulfide bonds (2)

Type	Positions
Disulfide bond	152–181, 153–167

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	52, 53

Mutagenesis-validated functional residues (6)

Position	Phenotype
9	loss of palmitoylation; when associated with a-78; a-79; a-87; a-218 and a-219.
78	loss of palmitoylation; when associated with a-9; a-79; a-87; a-218 and a-219.
79	loss of palmitoylation; when associated with a-9; a-78; a-87; a-218 and a-219.
87	loss of palmitoylation; when associated with a-9; a-78; a-79; a-218 and a-219.
218	loss of palmitoylation; when associated with a-9; a-78; a-79; a-87 and a-219.
219	loss of palmitoylation; when associated with a-9; a-78; a-79; a-87 and a-218.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 12; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-5336415	Uptake and function of diphtheria toxin ⚕	curated
R-HSA-1300645	Acrosome Reaction and Sperm:Oocyte Membrane Binding	curated
R-HSA-114608	Platelet degranulation	curated
R-HSA-9824439	Bacterial Infection Pathways ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-5339562	Uptake and actions of bacterial toxins ⚕	—
R-HSA-1187000	Fertilization	—
R-HSA-109582	Hemostasis	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-1474165	Reproduction	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—

MSigDB gene sets: 544 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_SINGLE_FERTILIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, LEE_NEURAL_CREST_STEM_CELL_DN, CHIBA_RESPONSE_TO_TSA_UP, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_MYELOID_LEUKOCYTE_MIGRATION, MACLACHLAN_BRCA1_TARGETS_DN, GOBP_REGULATION_OF_COAGULATION, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION

GO Biological Process (15): cell adhesion (GO:0007155), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), glial cell migration (GO:0008347), oligodendrocyte development (GO:0014003), myoblast fusion involved in skeletal muscle regeneration (GO:0014905), platelet activation (GO:0030168), paranodal junction assembly (GO:0030913), receptor internalization (GO:0031623), sperm-egg recognition (GO:0035036), cellular response to low-density lipoprotein particle stimulus (GO:0071404), negative regulation of platelet aggregation (GO:0090331), regulation of macrophage migration (GO:1905521), single fertilization (GO:0007338), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (2): integrin binding (GO:0005178), protein binding (GO:0005515)

GO Cellular Component (13): plasma membrane (GO:0005886), focal adhesion (GO:0005925), external side of plasma membrane (GO:0009897), membrane (GO:0016020), apical plasma membrane (GO:0016324), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), platelet alpha granule membrane (GO:0031092), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), extracellular vesicle (GO:1903561), extracellular region (GO:0005576), cell surface (GO:0009986)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Fertilization	1
Uptake and actions of bacterial toxins	1
Reproduction	1
Bacterial Infection Pathways	1
Disease	1
Hemostasis	1
Platelet activation, signaling and aggregation	1
Infectious disease	1

GO top-level categories

55 GO namespaces:

Category	Terms
cellular anatomical structure	3
single fertilization	2
cellular process	1
cellular process involved in reproduction in multicellular organism	1
cell migration	1
gliogenesis	1
glial cell development	1
oligodendrocyte differentiation	1
myoblast fusion	1
myotube differentiation involved in skeletal muscle regeneration	1
skeletal muscle tissue regeneration	1
cell activation	1
blood coagulation	1
cell-cell junction assembly	1
cellular component assembly involved in morphogenesis	1
myelin assembly	1
receptor-mediated endocytosis	1
cell-cell recognition	1
response to lipoprotein particle	1
cellular response to lipoprotein particle stimulus	1
negative regulation of platelet activation	1
negative regulation of homotypic cell-cell adhesion	1
platelet aggregation	1
regulation of platelet aggregation	1
regulation of mononuclear cell migration	1
macrophage migration	1
fertilization	1
system development	1
animal gross anatomical part developmental process	1
cellular developmental process	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
binding	1
membrane	1
cell periphery	1
cell-substrate junction	1
plasma membrane	1
cell surface	1
side of membrane	1
apical part of cell	1
plasma membrane region	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1
secretory granule membrane	1
platelet alpha granule	1
cellular_component	1
extracellular vesicle	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
cell adhesion	BP	direct assay
fusion of sperm to egg plasma membrane involved in single fertilization	BP	direct assay
glial cell migration	BP	mutant phenotype
negative regulation of platelet aggregation	BP	direct assay
extracellular exosome	CC	direct assay
extracellular vesicle	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
plasma membrane	CC	direct assay
protein-containing complex	CC	direct assay
integrin binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,944 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD9	TSG101	Q99816	922
CD9	PTGFRN	Q9P2B2	893
CD9	IGSF8	Q969P0	862
CD9	CANX	P27824	817
CD9	FLOT1	O75955	764
CD9	HSPA4	P34932	741
CD9	SDCBP	O00560	736
CD9	PDCD6IP	Q8WUM4	733
CD9	DDX1	Q92499	720
CD9	ITGA6	P23229	718
CD9	CD44	P16070	712
CD9	CD81	P18582	704
CD9	GAPDH	P00354	696
CD9	ITGB1	P05556	694
CD9	SDCBP2	Q9H190	689

IntAct

Human interaction partners of CD9 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
PTGFRN	physical association	0.860	3
IGSF8	association	0.760	2
ADAM10	association	0.750	15
ITGB1	association	0.690	1
ODF4	physical association	0.560	3
MME	physical association	0.500	4
SRGAP1	physical association	0.400	1
NSA2	association	0.350	1

BioGRID (133 interactions; top human partners by supporting records): PTGFRN (Affinity Capture-Western; 7 records), IGSF8 (Affinity Capture-MS; 5 records), CD81 (Affinity Capture-Western; 4 records), SLC22A2 (PCA; 3 records), ADRB2 (PCA; 2 records), CD46 (Affinity Capture-Western; 2 records), CD63 (Affinity Capture-Western; 2 records), DPP4 (Affinity Capture-Western; 2 records), IL6ST (Affinity Capture-Western; 2 records), ITGA3 (Affinity Capture-Western; 2 records), ITGB1 (Affinity Capture-Western; 2 records), KIT (Affinity Capture-Western; 2 records), TSPAN4 (Affinity Capture-Western; 2 records), ACE2 (Affinity Capture-Western), ACIN1 (Co-fractionation)

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
★ ITGA2b-ITGB3-CD9-GP1b-CD47 complex	5	CD47, CD9, GP1BA, ITGA2B, ITGB3
★ CD38-CD9-HLA-DR complex	4	CD38, CD9, HLA-DRA, HLA-DRB1
★ ITGA2B-ITGB3-CD9 complex	3	CD9, ITGA2B, ITGB3
★ ITGA7-ITGB1-CD9 complex	3	CD9, ITGA7, ITGB1
ITGA6-ITGB4-CD9 complex	3	CD9, ITGA6, ITGB4

Disease & clinical

Genetic variants

Variant evidence for CD9: 24 ClinVar records (0 pathogenic / likely pathogenic); 9 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	0
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 42 predictions of 713):

Position(s)	Effect	Δscore	Sites
12:6225535–6225536	donor_loss	1.0000	5
12:6232630–6232631	acceptor_loss	1.0000	5
12:6232730–6232731	donor_loss	1.0000	5
12:6233410–6233411	acceptor_loss	1.0000	6
12:6233487–6233488	donor_loss	1.0000	3
12:6235227–6235228	acceptor_loss	1.0000	5
12:6235328–6235329	donor_loss	1.0000	3
12:6236190	acceptor_gain	1.0000
12:6236190–6236191	acceptor_loss	1.0000	4
12:6200566–6200567	donor_loss	0.9900	5

AlphaMissense

812 missense substitutions predicted likely pathogenic (of 1,519 scored), across 181 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M207	9	0.945	0.999
M211	9	0.942	0.999
M70	9	0.881	0.998
M215	9	0.841	0.993
F93	8	0.964	0.997
D38	8	0.963	0.993
F92	8	0.957	0.999
F100	8	0.954	0.987
F75	8	0.950	0.995
F21	8	0.949	0.990
N18	8	0.947	0.999
S214	8	0.931	0.999
F17	8	0.927	0.989
F15	8	0.926	0.987
F45	8	0.916	0.988
F56	8	0.916	0.993
F189	8	0.914	0.981
F213	8	0.911	0.970
H147	8	0.900	0.986
C152	7	0.998	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.87e-06
Kidney Renal Clear Cell Carcinoma (validation)	favorable	3.24e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000107
Glioblastoma Multiforme (validation)	unfavorable	0.000496
Lung Squamous Cell Carcinoma (TCGA)	favorable	0.000509

Disease associations

OMIM: gene MIM:143030 | disease phenotypes:

GWAS associations

9 associations:

Study	Trait	p-value
GCST004599_131	Mean platelet volume	2e-25
GCST001335_11	Mean platelet volume	2e-21
GCST90002395_704	Mean platelet volume	1e-20
GCST001337_34	Platelet count	4e-11
GCST007856_18	Colorectal cancer or advanced adenoma	3e-10
GCST002454_10	Colorectal cancer	6e-10
GCST007856_2	Colorectal cancer or advanced adenoma	1e-8
GCST003383_12	Platelet count	2e-7
GCST002074_7	Paclitaxel-induced neuropathy	4e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, increases methylation, affects cotreatment	9
Benzo(a)pyrene	affects methylation, increases expression	7
Tretinoin	decreases expression, increases expression	5
trichostatin A	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	4
Particulate Matter	increases abundance, affects cotreatment, increases expression, decreases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
Vorinostat	increases expression, affects cotreatment, affects expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation, decreases expression	3
Smoke	decreases expression, increases abundance, increases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	increases abundance, affects methylation, decreases expression	2
Vehicle Emissions	affects cotreatment, decreases expression, increases abundance, increases expression	2
Doxorubicin	increases expression	2
Lead	affects expression, decreases expression	2
Rotenone	decreases expression, increases expression	2
Tetradecanoylphorbol Acetate	increases expression, affects cotreatment, affects expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Zinc	affects cotreatment, affects expression, increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
tert-Butylhydroperoxide	affects expression, decreases expression	2
Vitamin K 3	affects expression	2
bisphenol F	affects cotreatment, decreases expression	1

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1JB	OS3-R5-GFP-CD9	Cancer cell line	Sex unspecified
CVCL_B1ES	Abcam A-549 CD9 KO	Cancer cell line	Male
CVCL_B1MU	Abcam HeLa CD9 KO	Cancer cell line	Female
CVCL_D7M9	Ubigene A-549 CD9 KO	Cancer cell line	Male
CVCL_E1EB	Ubigene U-87 MG CD9 KO	Cancer cell line	Male
CVCL_E3FA	OS3-R5-pZCD9	Cancer cell line	Sex unspecified
CVCL_F6JK	EDITGENE CD9 Knockout HEK293 Cell Line	Transformed cell line	Female
CVCL_SI00	HAP1 CD9 (-) 1	Cancer cell line	Male
CVCL_XM62	HAP1 CD9 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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