ADGRE2

Summary

ADGRE2 (adhesion G protein-coupled receptor E2, HGNC:3337) is a protein-coding gene on chromosome 19p13.12, encoding Adhesion G protein-coupled receptor E2 (Q9UHX3). Cell surface receptor that binds to the chondroitin sulfate moiety of glycosaminoglycan chains and promotes cell attachment.

This gene encodes a member of the class B seven-span transmembrane (TM7) subfamily of G-protein coupled receptors. These proteins are characterized by an extended extracellular region with a variable number of N-terminal epidermal growth factor-like domains coupled to a TM7 domain via a mucin-like spacer domain. The encoded protein is expressed mainly in myeloid cells where it promotes cell-cell adhesion through interaction with chondroitin sulfate chains. This gene is situated in a cluster of related genes on chromosome 19. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 30817 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant vibratory urticaria (Supportive, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 687 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_013447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3337
Approved symbol	ADGRE2
Name	adhesion G protein-coupled receptor E2
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	CD312
Ensembl gene	ENSG00000127507
Ensembl biotype	protein_coding
OMIM	606100
Entrez	30817

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000315576, ENST00000360222, ENST00000392962, ENST00000392965, ENST00000594076, ENST00000594294, ENST00000595208, ENST00000595839, ENST00000596991, ENST00000598500, ENST00000599423, ENST00000601345, ENST00000601619, ENST00000904386, ENST00000904387, ENST00000904388, ENST00000904389, ENST00000904390, ENST00000938770, ENST00000938771, ENST00000944172

RefSeq mRNA: 4 — MANE Select: NM_013447 NM_001271052, NM_013447, NM_152916, NM_152917

CCDS: CCDS32933, CCDS32934, CCDS32935, CCDS59361

Canonical transcript exons

ENST00000315576 — 21 exons

Exon	Start	End
ENSE00001273581	14755654	14755877
ENSE00001701230	14766235	14766381
ENSE00001737543	14732392	14736244
ENSE00002272414	14778257	14778560
ENSE00003483450	14754954	14755127
ENSE00003532482	14765524	14765570
ENSE00003540226	14746232	14746323
ENSE00003541426	14743616	14743784
ENSE00003555148	14751436	14751671
ENSE00003564245	14756238	14756345
ENSE00003574549	14772342	14772497
ENSE00003599880	14746896	14746962
ENSE00003603400	14766978	14767109
ENSE00003625736	14776726	14776927
ENSE00003626493	14765658	14765804
ENSE00003630628	14752329	14752526
ENSE00003634486	14773938	14774054
ENSE00003647085	14765320	14765397
ENSE00003670818	14743420	14743530
ENSE00003682970	14774256	14774306
ENSE00003691345	14764433	14764610

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 94.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.2410 / max 1263.2222, expressed in 1317 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179676	23.4613	1307
179678	0.5539	125
179677	0.1752	79
179679	0.0284	11
179680	0.0223	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.42	gold quality
blood	UBERON:0000178	94.20	gold quality
mononuclear cell	CL:0000842	94.05	gold quality
leukocyte	CL:0000738	93.93	gold quality
granulocyte	CL:0000094	91.05	gold quality
spleen	UBERON:0002106	86.57	gold quality
vermiform appendix	UBERON:0001154	80.04	gold quality
periodontal ligament	UBERON:0008266	79.93	gold quality
endometrium epithelium	UBERON:0004811	78.37	gold quality
upper lobe of left lung	UBERON:0008952	76.98	gold quality
palpebral conjunctiva	UBERON:0001812	76.71	gold quality
right lung	UBERON:0002167	76.08	gold quality
upper lobe of lung	UBERON:0008948	76.08	gold quality
gall bladder	UBERON:0002110	73.85	gold quality
caecum	UBERON:0001153	73.49	gold quality
bone marrow cell	CL:0002092	71.84	gold quality
bone marrow	UBERON:0002371	71.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.38	silver quality
left adrenal gland cortex	UBERON:0035825	70.89	gold quality
left adrenal gland	UBERON:0001234	70.68	gold quality
right coronary artery	UBERON:0001625	70.38	gold quality
lymph node	UBERON:0000029	69.24	gold quality
colonic epithelium	UBERON:0000397	68.74	gold quality
sperm	CL:0000019	68.33	gold quality
adrenal cortex	UBERON:0001235	68.29	gold quality
metanephros cortex	UBERON:0010533	68.21	gold quality
lung	UBERON:0002048	68.20	gold quality
rectum	UBERON:0001052	67.80	gold quality
right adrenal gland	UBERON:0001233	67.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	67.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.53
E-MTAB-8498	yes	10.75
E-MTAB-6678	no	3.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting ADGRE2, 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-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735

Literature-anchored findings (GeneRIF, showing 24)

• epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans (PMID:12829604)
• role of the extracellular stalk and the G protein-coupled receptor proteolysis site motif in EMR2 processing (PMID:12860403)
• Site-directed mutagenesis of the P(+1) cleavage site (Ser(518)) shows an absolute requirement of a Ser, Thr, or Cys residue for efficient proteolysis. (PMID:15150276)
• The results presented here further support the idea that EMR2 plays a role in the migration and adhesion of myeloid cells during cell differentiation, maturation, and activation. (PMID:17174274)
• Here we demonstrate how the human-restricted adhesion-GPCR EMR2 regulates neutrophil responses by potentiating the effects of a number of proinflammatory mediators and show that the transmembrane region is critical for adhesion-GPCR function. (PMID:17928360)
• EGF-TM7 pre-mRNAs also undergo the rare trans-splicing, leading to the generation of functional chimeric receptors. (PMID:18267122)
• complex cellular expression programmes rather than activation modes regulate the expression of EGF-TM7 receptors in macrophages (PMID:20167235)
• The association of improved patient survival with higher nuclear expression levels identifies EMR2 as a potential biomarker in patients with invasive breast cancer. (PMID:21174063)
• High EMR2 is associated with invasive phenotype in glioblastoma. (PMID:21503828)
• a functional role for EMR2 in the modulation of neutrophil activation during inflammation. (PMID:22035891)
• Using the myeloid cell-restricted EMR2 receptor as a paradigm, we exam the mechanistic relevance of the subunit interaction and demonstrate a critical role for autoproteolysis in mediating receptor signaling and cell activation (PMID:22310662)
• Data suggest that blood neutrophils expressing CD11c antigen and EMR2 protein be considered as potential biomarkers for sepsis and systemic inflammatory response syndrome (SIRS), respectively. (PMID:26153037)
• We identified a previously unknown missense substitution in ADGRE2 which was predicted to result in the replacement of cysteine with tyrosine as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. (PMID:26841242)
• EMR2 expression levels correlated with CTP scores and increased further in cirrhotic patients with infections. These high EMR2-expressed neutrophils had activated phenotype but with deranged functions. Higher levels of these EMR2-expressed neutrophils correlated with infectious complications and predict mortality. (PMID:27905560)
• miR-99a reveals two novel targets E2F2 and EMR2 that play a key role in lung tumourigenesis. By inhibiting E2F2 and EMR2, miR-99a represses in vivo the transition of epithelial cells through an EMT process concomitantly with the inhibition of stemness features and consequently decreasing the CSC population. (PMID:29072692)
• Results show that the membrane-associated EMR2-NTF displays a distinct N-glycosylation pattern. Moreover, its membrane-association ability is found to be regulated by site-specific N-glycosylation in the GAIN domain. The membrane-association of EMR2-NTF takes place in post-ER compartments and identify a unique amphipathic alpha-helix at the GAIN sub-domain A as a putative in-plane membrane anchor. (PMID:29540735)
• The ADGRE2 mutation causing familiar vibratory angioedema is not responsible for the frequent nonfamilial form. (PMID:30445064)
• EMR2 stimulates tumor angiogenesis through RGD motif-dependent mechanism.EMR2 promotes tumor angiogenesis by overexpressing MMP-9. (PMID:31594642)
• G Protein-Coupling of Adhesion GPCRs ADGRE2/EMR2 and ADGRE5/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody. (PMID:31969668)
• Critical Signaling Events in the Mechanoactivation of Human Mast Cells through p.C492Y-ADGRE2. (PMID:32222457)
• Stimulation of Vibratory Urticaria-Associated Adhesion-GPCR, EMR2/ADGRE2, Triggers the NLRP3 Inflammasome Activation Signal in Human Monocytes. (PMID:33488598)
• Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain. (PMID:33497605)
• The Posttraumatic Increase in the Adhesion of GPCR EMR2/ADGRE2 to Circulating Neutrophils Is Not Related to Injury Severity. (PMID:37998392)
• Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia. (PMID:39082681)

Cross-species orthologs

0 orthologs

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), ADGRE5 (ENSG00000123146), 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 E2 — Q9UHX3 (reviewed: Q9UHX3)

Alternative names: EGF-like module receptor 2, EGF-like module-containing mucin-like hormone receptor-like 2

All UniProt accessions (4): Q9UHX3, B4DWB8, M0QY55, M0R0K5

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor that binds to the chondroitin sulfate moiety of glycosaminoglycan chains and promotes cell attachment. Promotes granulocyte chemotaxis, degranulation and adhesion. In macrophages, promotes the release of inflammatory cytokines, including IL8 and TNF. Signals probably through G-proteins. Is a regulator of mast cell degranulation.

Subunit / interactions. Forms a heterodimer, consisting of a large extracellular region non-covalently linked to a seven-transmembrane moiety. Interacts with chondroitin sulfate; the interaction with chondroitin sulfate is calcium-dependent. Interacts with CD55.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane.

Tissue specificity. Expression is restricted to myeloid cells. Highest expression was found in peripheral blood leukocytes, followed by spleen and lymph nodes, with intermediate to low levels in thymus, bone marrow, fetal liver, placenta, and lung, and no expression in heart, brain, skeletal muscle, kidney, or pancreas. Expression is also detected in monocyte/macrophage and Jurkat cell lines but not in other cell lines tested. High expression in mast cells.

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

Disease relevance. Vibratory urticaria (VBU) [MIM:125630] An autosomal dominant disorder characterized by localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The GPS region of the GAIN-B domain is necessary, but not sufficient for receptor cleavage, which require the entire extracellular stalk. Binding to chondroitin sulfate is mediated by the fourth EGF domain.

Miscellaneous. Has no murine ortholog.

Similarity. Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9UHX3-1	1	yes
Q9UHX3-2	2
Q9UHX3-3	3
Q9UHX3-4	4
Q9UHX3-5	5
Q9UHX3-6	6

RefSeq proteins (4): NP_001257981, NP_038475, NP_690880, NP_690881 (=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 (81 total): disulfide bond 17, strand 14, topological domain 8, glycosylation site 8, transmembrane region 7, domain 6, sequence variant 6, splice variant 5, sequence conflict 2, helix 2, signal peptide 1, chain 1, region of interest 1, site 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2BOU	X-RAY DIFFRACTION	1.9
2BOX	X-RAY DIFFRACTION	2.5
2BO2	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHX3-F1	79.44	0.17

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): 517–518 (cleavage; by autolysis)

Disulfide bonds (17): 29–39, 33–45, 47–65, 71–85, 79–94, 96–117, 123–136, 130–145, 147–161, 167–180, 174–189, 191–210, 216–229, 223–238, 240–259, 482–512, 500–514

Glycosylation sites (8): 41, 111, 206, 298, 347, 354, 456, 460

Mutagenesis-validated functional residues (1):

Position	Phenotype
518	abolishes cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 207 (showing top): GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, ONDER_CDH1_TARGETS_3_DN, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, GOBP_MAST_CELL_ACTIVATION, GOBP_EXOCYTOSIS

GO Biological Process (9): inflammatory response (GO:0006954), cell adhesion (GO:0007155), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), cell migration (GO:0016477), regulation of mast cell degranulation (GO:0043304), granulocyte chemotaxis (GO:0071621), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (5): G protein-coupled receptor activity (GO:0004930), calcium ion binding (GO:0005509), chondroitin sulfate binding (GO:0035374), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), membrane (GO:0016020), leading edge membrane (GO:0031256), ruffle membrane (GO:0032587), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GPCR ligand binding	1
Signal Transduction	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	2
signal transduction	2
defense response	1
G protein-coupled receptor activity	1
cell motility	1
regulation of myeloid leukocyte mediated immunity	1
regulation of leukocyte degranulation	1
mast cell degranulation	1
leukocyte chemotaxis	1
granulocyte migration	1
biological_process	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell leading edge	1
ruffle	1
cell projection membrane	1
leading edge membrane	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRE2	CD55	P08174	998
ADGRE2	LPAR1	P78351	963
ADGRE2	GNA12	Q03113	773
ADGRE2	CD59	P13987	756
ADGRE2	SCT	P09683	612
ADGRE2	CXADR	P78310	588
ADGRE2	THY1	P04216	565
ADGRE2	ITGAM	P11215	561
ADGRE2	CD44	P16070	558
ADGRE2	CD46	P15529	554
ADGRE2	CD33	P20138	535
ADGRE2	RFX1	P22670	513
ADGRE2	CD37	P11049	491
ADGRE2	TLR4	O00206	473
ADGRE2	SELP	P16109	457

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
CFHR1	ADGRE2	psi-mi:“MI:0407”(direct interaction)	0.630
CFHR1	ADGRE2	psi-mi:“MI:0915”(physical association)	0.630
CFHR1	ADGRE2	psi-mi:“MI:2364”(proximity)	0.630
ADGRE2	MTERF3	psi-mi:“MI:0915”(physical association)	0.560
ADGRE2	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
ADGRE2	SLC7A14	psi-mi:“MI:0915”(physical association)	0.560
ADGRE2	MARCHF6	psi-mi:“MI:0915”(physical association)	0.560
ADGRE2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
ADGRE2	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
BIK	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
MARCHF6	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
TMEM80	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
AQP6	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
MMGT1	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
MTERF3	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
CCDC107	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
ELOVL4	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL3	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
TLCD4	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
MFSD5	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (38): EMR2 (Affinity Capture-MS), EMR2 (Affinity Capture-MS), EMR2 (Two-hybrid), EMR2 (Two-hybrid), EMR2 (Two-hybrid), EMR2 (Two-hybrid), EMR2 (Two-hybrid), EMR2 (Two-hybrid), EMR2 (Two-hybrid), MARCH6 (Two-hybrid), TMEM56 (Two-hybrid), MTERF3 (Two-hybrid), CREB3L1 (Two-hybrid), FCER1G (Two-hybrid), CCDC107 (Two-hybrid)

ESM2 similar proteins: A0JND9, A6H730, A6H757, B1H1P9, D3YTS9, E1BPW0, O35795, O55026, O75356, P08648, P11117, P11688, P15309, P16301, P17405, P18424, P20611, P20646, P24638, P51993, P53761, P56433, P58242, Q04519, Q0P5F0, Q0VD19, Q11126, Q11128, Q3KQG9, Q4R5N9, Q5DRK1, Q5MY95, Q5NVF6, Q5R8C0, Q5RK23, Q6P6S9, Q7RTX1, Q8CE08, Q8HYJ5, Q8HYJ7

Diamond homologs: A0A6I8RMG7, A2AJ76, B3EWY9, B5DFC9, O35568, O77469, O88322, P10493, P14543, P41413, P48960, P98095, Q04592, Q09165, Q14112, Q19267, Q2KIT5, Q2Q421, Q2Q426, Q4G063, Q4V7F2, Q4V7M2, Q5EA46, Q5RBP1, Q5XH36, Q60438, Q6UXH1, Q6UXI9, Q7SXF6, Q7ZXL5, Q86XX4, Q8BPB5, Q8K4G1, Q8R4U0, Q8R4Y4, Q91XD7, Q96HD1, Q96RW7, Q9CYA0, Q9JJS0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	366
Likely benign	203
Benign	67

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
144765	GRCh38/hg38 19p13.12-13.11(chr19:14154962-16914313)x1	Pathogenic
146686	GRCh38/hg38 19p13.2-13.12(chr19:12580427-14742673)x1	Pathogenic
147284	GRCh38/hg38 19p13.13-13.12(chr19:13533925-15371089)x1	Pathogenic
442476	GRCh37/hg19 19p13.12-13.11(chr19:14883158-16788770)x1	Pathogenic
59112	GRCh38/hg38 19p13.2-13.12(chr19:12132052-14751798)x3	Pathogenic
816068	GRCh37/hg19 19p13.12(chr19:14368330-15712368)x1	Pathogenic
3765553	NM_013447.4(ADGRE2):c.1276C>T (p.Gln426Ter)	Likely pathogenic

SpliceAI

2660 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14743419:CCGTG:C	donor_gain	1.0000
19:14746811:T:TA	donor_gain	1.0000
19:14746891:CTCA:C	donor_loss	1.0000
19:14746892:TCACA:T	donor_loss	1.0000
19:14746893:CA:C	donor_loss	1.0000
19:14746894:A:AC	donor_gain	1.0000
19:14746894:ACA:A	donor_loss	1.0000
19:14746895:C:CG	donor_gain	1.0000
19:14746963:C:CC	acceptor_gain	1.0000
19:14751434:A:AC	donor_gain	1.0000
19:14751435:C:CC	donor_gain	1.0000
19:14752535:C:CT	acceptor_gain	1.0000
19:14752535:C:T	acceptor_gain	1.0000
19:14752536:G:T	acceptor_gain	1.0000
19:14755124:CTGA:C	acceptor_gain	1.0000
19:14755128:C:CC	acceptor_gain	1.0000
19:14755653:CA:C	donor_gain	1.0000
19:14764428:CCTA:C	donor_loss	1.0000
19:14764429:CTA:C	donor_loss	1.0000
19:14764430:TA:T	donor_loss	1.0000
19:14764431:A:AT	donor_loss	1.0000
19:14764606:ATGCT:A	acceptor_gain	1.0000
19:14764607:TGCT:T	acceptor_gain	1.0000
19:14764609:CT:C	acceptor_gain	1.0000
19:14764611:C:CC	acceptor_gain	1.0000
19:14765315:CTTA:C	donor_loss	1.0000
19:14765316:TTACC:T	donor_loss	1.0000
19:14765318:A:AC	donor_gain	1.0000
19:14765318:AC:A	donor_gain	1.0000
19:14765319:C:A	donor_loss	1.0000

AlphaMissense

5402 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:14755059:C:A	W495C	0.991
19:14755059:C:G	W495C	0.991
19:14773984:G:C	F51L	0.984
19:14773984:G:T	F51L	0.984
19:14773986:A:G	F51L	0.984
19:14766240:C:G	C210S	0.977
19:14766241:A:T	C210S	0.977
19:14766369:C:G	C167S	0.976
19:14766370:A:T	C167S	0.976
19:14772347:C:G	C117S	0.974
19:14772348:A:T	C117S	0.974
19:14773997:C:G	C47S	0.974
19:14773998:A:T	C47S	0.974
19:14766303:C:G	C189S	0.973
19:14766304:A:T	C189S	0.973
19:14766330:C:G	C180S	0.973
19:14766331:A:T	C180S	0.973
19:14766241:A:G	C210R	0.972
19:14772485:C:G	C71S	0.972
19:14772486:A:T	C71S	0.972
19:14755061:A:G	W495R	0.971
19:14755061:A:T	W495R	0.971
19:14755089:C:A	W485C	0.971
19:14755089:C:G	W485C	0.971
19:14765753:C:G	C229S	0.971
19:14765754:A:T	C229S	0.971
19:14765792:C:G	C216S	0.971
19:14765793:A:T	C216S	0.971
19:14766284:C:A	W195C	0.971
19:14766284:C:G	W195C	0.971

dbSNP variants (sampled 300 via entrez): RS1000013688 (19:14779783 A>G), RS1000073964 (19:14780050 G>A), RS1000082572 (19:14774452 G>A,C,T), RS1000147360 (19:14759860 C>A,T), RS1000161792 (19:14752274 A>G), RS1000254306 (19:14754696 A>G), RS1000263953 (19:14760008 TG>T), RS1000363831 (19:14743980 C>T), RS1000412058 (19:14769949 C>G,T), RS1000451106 (19:14741232 G>A), RS1000507656 (19:14766076 C>A,T), RS1000608711 (19:14729372 G>GT), RS1000739800 (19:14771021 T>A,C), RS1000768489 (19:14765837 C>A,T), RS1000798363 (19:14724794 G>A,T)

Disease associations

OMIM: gene MIM:606100 | disease phenotypes: MIM:125630, MIM:193050

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant vibratory urticaria	Supportive	Autosomal dominant

Mondo (2): vibratory urticaria (MONDO:0006618), autosomal dominant vibratory urticaria (MONDO:0007447)

Orphanet (1): Vibratory urticaria (Orphanet:493342)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001025	Urticaria
HP:0001041	Facial erythema
HP:0011971	Dermatographic urticaria
HP:0031284	Flushing

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004363_1	Plasma androstenedione levels in resected early stage-receptor positive breast cancer	1.000000e-07
GCST005547_12	Major depressive disorder	1.000000e-06
GCST006585_2458	Blood protein levels	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007972	androstenedione measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536347	Vibratory angioedema (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Adhesion Class GPCRs

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
sodium arsenite	decreases expression, affects expression, affects methylation	3
Nickel	decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
propionaldehyde	increases expression	2
butyraldehyde	increases expression	2
pentanal	increases expression	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
n-hexanal	increases expression	1
trichostatin A	increases expression	1
3,4-dichloroaniline	increases expression	1
beta-lapachone	increases expression	1
aflatoxin B2	increases methylation	1
caprylic aldehyde	increases expression	1
heptanal	increases expression	1
avobenzone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Air Pollutants, Occupational	decreases expression	1
Cadmium	increases expression	1
Diuron	increases expression	1
Endosulfan	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methotrexate	decreases expression	1
Ozone	increases expression	1
Silicon Dioxide	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1S3	HyCyte MOLM-13 KO-hADGRE2	Cancer cell line	Male

Clinical trials (associated diseases)

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