ADGRE5

Summary

ADGRE5 (adhesion G protein-coupled receptor E5, HGNC:1711) is a protein-coding gene on chromosome 19p13.12, encoding Adhesion G protein-coupled receptor E5 (P48960). Receptor potentially involved in both adhesion and signaling processes early after leukocyte activation.

This gene encodes a member of the EGF-TM7 subfamily of adhesion G protein-coupled receptors, which mediate cell-cell interactions. These proteins are cleaved by self-catalytic proteolysis into a large extracellular subunit and seven-span transmembrane subunit, which associate at the cell surface as a receptor complex. The encoded protein may play a role in cell adhesion as well as leukocyte recruitment, activation and migration, and contains multiple extracellular EGF-like repeats which mediate binding to chondroitin sulfate and the cell surface complement regulatory protein CD55. Expression of this gene may play a role in the progression of several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms with 3 to 5 EGF-like repeats have been observed for this gene. This gene is found in a cluster with other EGF-TM7 genes on the short arm of chromosome 19.

Source: NCBI Gene 976 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 196 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_078481

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1711
Approved symbol	ADGRE5
Name	adhesion G protein-coupled receptor E5
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	TM7LN1
Ensembl gene	ENSG00000123146
Ensembl biotype	protein_coding
OMIM	601211
Entrez	976

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 16 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000242786, ENST00000357355, ENST00000358600, ENST00000586517, ENST00000586849, ENST00000587319, ENST00000587535, ENST00000587606, ENST00000587728, ENST00000590567, ENST00000591080, ENST00000591565, ENST00000591737, ENST00000592261, ENST00000592341, ENST00000593028, ENST00000877688, ENST00000877689, ENST00000877690, ENST00000922282, ENST00000952179, ENST00000952180, ENST00000952181, ENST00000952182, ENST00000952183, ENST00000952184

RefSeq mRNA: 3 — MANE Select: NM_078481 NM_001025160, NM_001784, NM_078481

CCDS: CCDS32929, CCDS32930, CCDS32931

Canonical transcript exons

ENST00000242786 — 20 exons

Exon	Start	End
ENSE00000836566	14401386	14401563
ENSE00000836567	14401653	14401760
ENSE00000836569	14402597	14402862
ENSE00000836572	14404383	14404562
ENSE00000836573	14405748	14405939
ENSE00000836576	14406331	14406557
ENSE00000836577	14406700	14406766
ENSE00000836579	14406869	14406960
ENSE00000836581	14407061	14407229
ENSE00001182776	14407908	14408009
ENSE00002770497	14381444	14381545
ENSE00002829109	14408092	14408723
ENSE00003470293	14397889	14397935
ENSE00003491526	14390924	14391079
ENSE00003504172	14388702	14388818
ENSE00003545641	14398062	14398139
ENSE00003576276	14388450	14388500
ENSE00003576861	14397658	14397804
ENSE00003659240	14396342	14396473
ENSE00003784965	14397077	14397223

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.7872 / max 1463.9219, expressed in 1683 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174239	32.7968	1382
174238	8.9696	1423
174235	3.4162	1080
174240	1.7868	860
174237	1.0107	388
174234	0.7526	115
174248	0.0545	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.27	gold quality
monocyte	CL:0000576	98.48	gold quality
leukocyte	CL:0000738	98.44	gold quality
mononuclear cell	CL:0000842	98.37	gold quality
ascending aorta	UBERON:0001496	98.10	gold quality
thoracic aorta	UBERON:0001515	98.08	gold quality
blood	UBERON:0000178	97.82	gold quality
descending thoracic aorta	UBERON:0002345	97.68	gold quality
body of uterus	UBERON:0009853	97.47	gold quality
spleen	UBERON:0002106	97.46	gold quality
right coronary artery	UBERON:0001625	97.25	gold quality
aorta	UBERON:0000947	96.64	gold quality
upper lobe of left lung	UBERON:0008952	96.51	gold quality
stromal cell of endometrium	CL:0002255	96.04	gold quality
right lung	UBERON:0002167	95.96	gold quality
upper lobe of lung	UBERON:0008948	95.81	gold quality
popliteal artery	UBERON:0002250	95.66	gold quality
tibial artery	UBERON:0007610	95.66	gold quality
left coronary artery	UBERON:0001626	95.51	gold quality
left uterine tube	UBERON:0001303	95.45	gold quality
mucosa of transverse colon	UBERON:0004991	95.12	gold quality
bone marrow cell	CL:0002092	94.70	gold quality
transverse colon	UBERON:0001157	94.59	gold quality
myometrium	UBERON:0001296	94.59	gold quality
coronary artery	UBERON:0001621	94.49	gold quality
vermiform appendix	UBERON:0001154	94.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.25	gold quality
saphenous vein	UBERON:0007318	94.13	gold quality
gall bladder	UBERON:0002110	93.56	gold quality
endocervix	UBERON:0000458	93.51	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-97	yes	742.55
E-MTAB-6701	yes	93.09
E-CURD-88	yes	47.40
E-CURD-122	yes	39.58
E-GEOD-135922	yes	27.79
E-MTAB-6678	yes	23.63
E-ANND-3	yes	13.74
E-CURD-114	yes	11.55
E-MTAB-9067	yes	3.65
E-GEOD-106540	no	939.53
E-GEOD-110499	no	474.63
E-CURD-11	no	106.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3, WT1

miRNA regulators (miRDB)

30 targeting ADGRE5, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-5579-3P	97.00	68.81	1111
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-8071	95.69	64.93	484
HSA-MIR-6823-3P	95.45	66.14	704
HSA-MIR-2114-3P	95.45	66.11	579

Literature-anchored findings (GeneRIF, showing 40)

• CD97 is expressed in all types of macrophages and dendritic cells except for microglia, in most T cells but only a few B cells, in smooth muscle cells, and in a restricted set of thyroid and gastrointestinal carcinomas. (PMID:11380941)
• CD97 expression correlates with dedifferentiation, migration, and invasion in colorectal tumor cell lines (PMID:12414513)
• coengagement of alpha5beta1 and chondroitotin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion (PMID:15576472)
• Findings suggest that CD97(EGF) may play a role in the development and invasion of gastric carcinomas. (PMID:16273233)
• CD55 engagement with its natural ligand CD97 can act as a potent costimulator of human CD4+ T cells, resulting in cellular activation and promoting enhanced proliferation and cytokine secretion. (PMID:16818763)
• enhanced CD97 expression in colorectal cancer cells is regulated independent of beta-catenin/Tcf-4, and is thus not a direct target of the canonical Wnt pathway (PMID:16929497)
• CD55 may simultaneously regulate both the innate and adaptive immune responses and can also regulate complement when bound to CD97. (PMID:17449467)
• EGF-TM7 pre-mRNAs also undergo the rare trans-splicing, leading to the generation of functional chimeric receptors. (PMID:18267122)
• Sp1 and Sp3 over-expression activates CD97 promoter activity in HEK293 cells. (PMID:18329191)
• CD97 is present on all lymphocytes in blood and lymphoid tissue. Expression of CD97 on B cells was lower compared to T and NK cells and did not differ between B-cell subsets. (PMID:19428565)
• CD97-mFc can adopt two different conformations; one capable of auto-proteolysis and the other not. (PMID:19737555)
• complex cellular expression programmes rather than activation modes regulate the expression of EGF-TM7 receptors in macrophages (PMID:20167235)
• Elevated expression of CD97 and its ligand CD55 at the invasion front correlate with tumor recurrence and metastasis, and CD95 may be a poor prognostic factor for rectal adenocarcinoma. (PMID:20339853)
• the tumor promoting role of CD97 small isoform in cancer progression (PMID:20428763)
• expression of the wild type - but not the GPS cleavage-deficient CD97 up-regulates the expression of N-cadherin, leading to Ca(++)-dependent cell-cell aggregation. (PMID:21156175)
• CD97 functioned to mediate invasion in prostate cancer cells, by associating with lysophosphatidic acid receptor 1 (LPAR1), leading to enhanced LPA-dependent RHO and extracellular signal-regulated kinase activation. (PMID:21978933)
• binding of leukocytes to activated endothelium mediated by the interaction of CD97 with Thy-1 is involved in firm adhesion of polymorphonuclear cells during inflammation and may play a role in the regulation of leukocyte trafficking to inflammatory sites. (PMID:22210915)
• we conclude that the possible upregulation of CD97 mediated by WT1 promotes cellular invasiveness-one of the most characteristic and challenging aspects of glial tumor cells. (PMID:22313360)
• CD97 and CD55 showed high expression at the invasive front of gallbladder carcinoma. CD97 and CD55 expression was associated with high histologic grade, advanced pathologic T stage, clinical stage and positive venous/lymphatic invasion. (PMID:22547928)
• CD97 small isoform not only supported gastric cancer local growth, but also promoted metastatic spread in orthotopically implanted mouse model. (PMID:22768192)
• CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. (PMID:22797060)
• CD97 expression promotes invasion and migration in glioblastoma multiforme, but has no effect on tumor proliferation. (PMID:23658650)
• study reports gene expression in skeletal muscle tissue of women with metabolic syndrome is enriched in inflammatory response-related genes; IL6R, HDAC9 and CD97 expression correlated negatively with insulin sensitivity; suggests a role for these 3 inflammatory genes in development of skeletal muscle insulin resistance in women (PMID:23771909)
• Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in a breast cancer cell line. (PMID:23838008)
• These results provide the first experimental evidence that cd97 is a direct target of miR-126. (PMID:24274104)
• We conclude that CD97 is located in the SR and at the peripheral sarcolemma of human and murine skeletal muscle, where its absence affects the structure of the SR without impairing skeletal muscle function (PMID:24949957)
• CD97 enhanced TIMP-2 secretion, leading to reduced MT-MMP-1 and -2 activities, impairing cell migration/invasion in vitro and lung macrometastasis in vivo and upregulating integrins. Both the NTF and the CTF of CD97 were required. (PMID:25174588)
• we identify the specific isoforms of CD97, a novel pro-invasive glioma antigen, across histologic grades of glioma and within BTICs. We also demonstrate a trend towards increased CD97 expression among the classical and mesenchymal GBM subtypes. (PMID:25714433)
• CD97 promotes gastric cancer cell proliferation and invasion in vitro through exosome-mediated MAPK signaling pathway, and exosomal miRNAs are probably involved in activation of the CD97-associated pathway. (PMID:26034356)
• present study suggested that the expressions of CD97 antigen and decay accelerating factor(DAF) were both upregulated in human cervical squamous cell carcinoma (PMID:26107567)
• High expression of CD97 is associated with lymphatic metastasis in gastric cancer. (PMID:26233326)
• Knock down of CD97 led to an altered mechanical phenotype, reduced adhesion to a stromal layer and lower wildtype FLT3 expression. (PMID:26462154)
• Biochemical features of the adhesion G protein-coupled receptor CD97 related to its auto-proteolysis and HeLa cell attachment activities (PMID:27641734)
• This study indicated that the CD97 and CD55 proteins might be reliable biomarkers to predict the metastasis status and prognosis of intrahepatic cholangiocarcinoma patients. (PMID:28345461)
• High CD97 expression Correlates with Breast, Colorectal and Pancreatic Cancer. (PMID:28373465)
• CD97 coordinates the coincidence of tumor cell migration and endothelial barrier retraction as a result of rapid bidirectional signaling between tumor cells and platelets. (PMID:29669286)
• CD97 as an effective potential prognosticator and therapeutic target for hepatocellular carcinoma. (PMID:29704239)
• High CD97 expression is associated with idiopathic pulmonary fibrosis. (PMID:29952218)
• Decreased migration and invasion was found in CD97 small isoform RNAi cervical carcinoma cells, with no change in cell proliferation. (PMID:30883974)
• Study identified ADREG5 as a MYC target gene able to discriminate between Burkitt lymphoma and diffuse large cell lymphoma (DLBCL) irrespectively of the presence of MYC breaks in DLBCL. (PMID:30953469)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-241f5.3	ENSDARG00000097680
mus_musculus	Adgre5	ENSMUSG00000002885
rattus_norvegicus	Adgre5	ENSRNOG00000004489

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Adhesion G protein-coupled receptor E5 — P48960 (reviewed: P48960)

Alternative names: Leukocyte antigen CD97

All UniProt accessions (4): P48960, K7EKV5, K7EPE8, K7EPP8

UniProt curated annotations — full annotation on UniProt →

Function. Receptor potentially involved in both adhesion and signaling processes early after leukocyte activation. Plays an essential role in leukocyte migration.

Subunit / interactions. Forms a heterodimer, consisting of a large extracellular region (alpha subunit) non-covalently linked to a seven-transmembrane moiety (beta subunit). Interacts with complement decay-accelerating factor (DAF). The largest isoform (isoform 1) interacts with chondroitin sulfate.

Subcellular location. Cell membrane Secreted. Extracellular space.

Tissue specificity. Broadly expressed, found on most hematopoietic cells, including activated lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. Expressed also abundantly by smooth muscle cells. Expressed in thyroid, colorectal, gastric, esophageal and pancreatic carcinomas too. Expression are increased under inflammatory conditions in the CNS of multiple sclerosis and in synovial tissue of patients with rheumatoid arthritis. Increased expression of CD97 in the synovium is accompanied by detectable levels of soluble CD97 in the synovial fluid.

Post-translational modifications. Proteolytically cleaved into 2 subunits, an extracellular alpha subunit and a seven-transmembrane subunit.

Domain organisation. The first two EGF domains mediate the interaction with DAF. A third tandemly arranged EGF domain is necessary for the structural integrity of the binding region. Binding to chondroitin sulfate is mediated by the fourth EGF domain.

Induction. Rapid up-regulation during lymphocyte activation.

Similarity. Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P48960-1	1, EGF(1,2,3,4,5)	yes
P48960-2	2, EGF(1,2,5)
P48960-3	3, EGF(1,2,3,5)

RefSeq proteins (3): NP_001020331, NP_001775, NP_510966* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000203	GPS	Conserved_site
IPR000742	EGF	Domain
IPR000832	GPCR_2_secretin-like	Family
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR003056	GPCR_2_ADGRE2_ADGRE5	Family
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF01825, PF07645

UniProt features (119 total): strand 27, helix 21, disulfide bond 17, glycosylation site 9, topological domain 8, transmembrane region 7, domain 6, modified residue 6, turn 4, chain 3, sequence conflict 3, region of interest 2, splice variant 2, signal peptide 1, compositionally biased region 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2BOU	X-RAY DIFFRACTION	1.9
8IKL	ELECTRON MICROSCOPY	2.33
7YDM	ELECTRON MICROSCOPY	2.89
7YDJ	ELECTRON MICROSCOPY	3.03
7YDH	ELECTRON MICROSCOPY	3.1
7YDP	ELECTRON MICROSCOPY	3.1
9MQR	ELECTRON MICROSCOPY	3.16
7DO4	X-RAY DIFFRACTION	3.2
8IKJ	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48960-F1	78.39	0.18

Antibody-complex structures (SAbDab): 5 — 7YDH, 7YDJ, 7YDM, 7YDP, 9MQR

Functional residue map

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

Catalytic / active sites (1): 530–531 (cleavage; by autolysis)

Post-translational modifications (6): 815, 816, 818, 825, 831, 833

Disulfide bonds (17): 26–36, 30–42, 44–62, 68–82, 76–91, 93–114, 120–133, 127–142, 144–158, 164–177, 171–186, 188–207, 213–226, 220–235, 237–256, 495–525, 513–527

Glycosylation sites (9): 33, 38, 108, 203, 371, 406, 413, 453, 520

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-6798695	Neutrophil degranulation
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-372790	Signaling by GPCR
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 313 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, MODULE_45, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, ONKEN_UVEAL_MELANOMA_UP, FISCHER_G2_M_CELL_CYCLE, GNF2_CD97, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP

GO Biological Process (8): inflammatory response (GO:0006954), immune response (GO:0006955), cell adhesion (GO:0007155), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), G protein-coupled receptor activity (GO:0004930), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), secretory granule membrane (GO:0030667), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
GPCR ligand binding	1
Innate Immune System	1
Immune System	1
Signal Transduction	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
signal transduction	2
cell communication	2
signaling	2
cellular anatomical structure	2
defense response	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
biological_process	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
metal ion binding	1
binding	1
membrane	1
cell periphery	1
cell-substrate junction	1
secretory granule	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

1317 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRE5	CD55	P08174	998
ADGRE5	LPAR1	P78351	965
ADGRE5	GNA12	Q03113	786
ADGRE5	CD59	P13987	775
ADGRE5	THY1	P04216	751
ADGRE5	SCT	P09683	733
ADGRE5	CXADR	P78310	636
ADGRE5	CD46	P15529	559
ADGRE5	CD44	P16070	556
ADGRE5	ITGAM	P11215	522
ADGRE5	ADGRB1	O14514	485
ADGRE5	SELP	P16109	461
ADGRE5	TLR4	O00206	459
ADGRE5	ITGAV	P06756	454
ADGRE5	CAV1	Q03135	448

IntAct

227 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
CD55	ADGRE5	psi-mi:“MI:0407”(direct interaction)	0.620
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM171	THAP12	psi-mi:“MI:0914”(association)	0.530
CYP2C9	CYP2C19	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
ATP1A3	AGPAT2	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
ADGRE5	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
LIN7C	ADGRE5	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRE5	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	ADGRE5	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRE5	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	ADGRE5	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRE5	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRE5	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
LNX2	ADGRE5	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (218): CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), CD97 (Affinity Capture-MS), TPST1 (Affinity Capture-MS), EMR2 (Affinity Capture-MS), NNT (Affinity Capture-MS), ADARB1 (Affinity Capture-MS), ZDHHC21 (Affinity Capture-MS), TMEM120B (Affinity Capture-MS), MTCH2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K1Q8, A3QNZ8, A3QNZ9, A3QP00, A3QP01, A3QP07, A3QP08, A3QP09, D4A3T6, E1BPQ3, E9Q4J9, E9Q6I0, G5ECB2, O35659, O62714, O70410, O75899, O88871, P32082, P35384, P41180, P43220, P48442, P48960, Q49HI0, Q58Y75, Q5T6X5, Q5U9X3, Q61606, Q6TAC4, Q70VB1, Q717C1, Q7RTX1, Q80T41, Q8BG22, Q8K385, Q8K4Z6, Q8R420, Q8SQA4, Q8TE23

Diamond homologs: A0A2Z2U4G9, A6QP74, O35659, O42602, O42603, O46502, O62772, O95838, P23811, P25107, P25117, P25961, P30082, P30083, P32082, P32215, P32241, P32301, P34998, P34999, P35000, P35347, P35353, P41586, P41587, P41588, P41593, P43218, P43219, P43220, P47866, P47871, P47872, P48546, P48960, P49190, P50133, P70205, P70555, P97751

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
hsa-mir-126-5p	“down-regulates quantity by repression”	ADGRE5	“post transcriptional regulation”
CD55	up-regulates	ADGRE5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 185 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Long-term potentiation	5	18.2×	1e-03
Assembly and cell surface presentation of NMDA receptors	8	15.5×	9e-06
Neurexins and neuroligins	9	13.5×	9e-06
Protein-protein interactions at synapses	6	12.2×	1e-03
Formation of the dystrophin-glycoprotein complex (DGC)	5	11.8×	4e-03
Class A/1 (Rhodopsin-like receptors)	9	5.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	30.8×	8e-09
protein localization to synapse	5	22.5×	4e-04
receptor clustering	6	22.0×	9e-05
establishment of cell polarity	5	11.3×	5e-03
bicellular tight junction assembly	5	9.7×	9e-03
receptor internalization	5	9.5×	9e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	7.7×	7e-03
establishment of localization in cell	8	7.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	149
Likely benign	19
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
443137	GRCh37/hg19 19p13.2-13.12(chr19:12574343-14726197)x1	Pathogenic
442731	GRCh37/hg19 19p13.2-13.12(chr19:13592592-14717528)x1	Likely pathogenic

SpliceAI

2272 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14381544:CGGTA:C	donor_loss	1.0000
19:14381546:G:GG	donor_gain	1.0000
19:14381546:GTA:G	donor_loss	1.0000
19:14388444:TTGCA:T	acceptor_loss	1.0000
19:14388445:TGCA:T	acceptor_loss	1.0000
19:14388446:GCAGC:G	acceptor_loss	1.0000
19:14388447:CAG:C	acceptor_loss	1.0000
19:14388448:A:AC	acceptor_loss	1.0000
19:14388448:A:AG	acceptor_gain	1.0000
19:14388449:G:GG	acceptor_gain	1.0000
19:14388449:G:GT	acceptor_loss	1.0000
19:14388449:GC:G	acceptor_gain	1.0000
19:14388449:GCA:G	acceptor_gain	1.0000
19:14388449:GCATT:G	acceptor_gain	1.0000
19:14388498:GGG:G	donor_gain	1.0000
19:14388499:GGG:G	donor_gain	1.0000
19:14388827:GCT:G	donor_gain	1.0000
19:14390920:CCAG:C	acceptor_loss	1.0000
19:14390921:CA:C	acceptor_loss	1.0000
19:14390922:A:AG	acceptor_gain	1.0000
19:14390923:G:GT	acceptor_gain	1.0000
19:14390923:GA:G	acceptor_gain	1.0000
19:14390923:GAC:G	acceptor_gain	1.0000
19:14390923:GACA:G	acceptor_gain	1.0000
19:14390923:GACAT:G	acceptor_gain	1.0000
19:14391077:AAGGT:A	donor_loss	1.0000
19:14391078:AG:A	donor_gain	1.0000
19:14391078:AGGTA:A	donor_loss	1.0000
19:14391079:GG:G	donor_gain	1.0000
19:14391079:GGT:G	donor_loss	1.0000

AlphaMissense

5483 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:14407188:G:C	G779R	0.998
19:14404457:G:C	W508C	0.997
19:14404457:G:T	W508C	0.997
19:14405823:T:C	F569L	0.997
19:14405825:C:A	F569L	0.997
19:14405825:C:G	F569L	0.997
19:14405875:T:C	L586P	0.997
19:14406394:T:A	W629R	0.997
19:14406394:T:C	W629R	0.997
19:14406497:C:A	P663H	0.997
19:14407110:T:A	W753R	0.997
19:14407110:T:C	W753R	0.997
19:14407188:G:T	G779C	0.997
19:14406400:A:C	S631R	0.996
19:14406402:C:A	S631R	0.996
19:14406402:C:G	S631R	0.996
19:14406497:C:G	P663R	0.996
19:14405799:T:C	C561R	0.995
19:14406419:T:C	L637P	0.995
19:14405813:C:G	C565W	0.994
19:14405879:C:G	C587W	0.994
19:14405883:T:C	C589R	0.994
19:14405887:T:C	L590P	0.994
19:14406409:G:C	G634R	0.994
19:14406485:G:A	G659D	0.994
19:14407101:G:C	G750R	0.994
19:14405869:T:C	L584P	0.993
19:14405907:T:C	F597L	0.993
19:14405909:C:A	F597L	0.993
19:14405909:C:G	F597L	0.993

dbSNP variants (sampled 300 via entrez): RS1000048124 (19:14408622 G>A,T), RS1000332293 (19:14388179 G>A), RS1000559493 (19:14393372 A>G), RS1000754494 (19:14387599 A>G), RS1000787069 (19:14387420 G>A), RS1000788877 (19:14399214 T>C), RS1000943673 (19:14404799 G>A,T), RS1000984103 (19:14387739 T>A), RS1000998444 (19:14398624 G>A), RS1001033429 (19:14393112 A>C), RS1001141943 (19:14398995 C>G,T), RS1001219600 (19:14397990 A>C), RS1001346428 (19:14392320 A>C), RS1001550329 (19:14387627 C>A), RS1001605639 (19:14398271 C>A,T)

Disease associations

OMIM: gene MIM:601211 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004599_143	Mean platelet volume	4.000000e-09
GCST90002388_42	Lymphocyte count	1.000000e-18
GCST90002393_647	Monocyte count	1.000000e-11
GCST90002395_402	Mean platelet volume	4.000000e-15
GCST90002395_403	Mean platelet volume	5.000000e-16
GCST90002401_253	Platelet distribution width	6.000000e-13
GCST90002401_254	Platelet distribution width	4.000000e-16
GCST90002407_365	White blood cell count	7.000000e-17

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523865 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Adhesion Class GPCRs

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.38	Kd	4152	nM	CHEMBL5653589
5.32	ED50	4812	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148031: Binding affinity to human CD97 incubated for 45 mins by Kinobead based pull down assay	kd	4.1519	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Air Pollutants	increases abundance, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Tretinoin	increases expression, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sulforaphane	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
avobenzone	increases expression	1
entinostat	increases expression	1
ICG 001	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression	1
Arsenic Trioxide	decreases expression	1
Troglitazone	decreases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Cadmium	increases abundance, increases expression	1
Calcitriol	increases expression	1
Copper	affects binding, increases expression	1
Demecolcine	increases expression	1
Disulfiram	affects binding, increases expression	1
Hydrocortisone	decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883339	Binding	PRESTO-Tango GPCRome screening (CD97)	Data for DCP probe UCSF924

Clinical trials (associated diseases)

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