RAMP2

Summary

RAMP2 (receptor activity modifying protein 2, HGNC:9844) is a protein-coding gene on chromosome 17q21.2, encoding Receptor activity-modifying protein 2 (O60895). Accessory protein that interacts with and modulates the function of G-protein coupled receptors including calcitonin gene-related peptide type 1 receptor (CALCRL) and calcitonin receptor (CALCR).

The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs). RAMPs are type I transmembrane proteins with an extracellular N terminus and a cytoplasmic C terminus. RAMPs are required to transport calcitonin-receptor-like receptor (CRLR) to the plasma membrane. CRLR, a receptor with seven transmembrane domains, can function as either a calcitonin-gene-related peptide (CGRP) receptor or an adrenomedullin receptor, depending on which members of the RAMP family are expressed. In the presence of this (RAMP2) protein, CRLR functions as an adrenomedullin receptor. The RAMP2 protein is involved in core glycosylation and transportation of adrenomedullin receptor to the cell surface.

Source: NCBI Gene 10266 — RefSeq curated summary.

At a glance

• Gene–disease (curated): open-angle glaucoma (Moderate, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 28 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005854

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9844
Approved symbol	RAMP2
Name	receptor activity modifying protein 2
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000131477
Ensembl biotype	protein_coding
OMIM	605154
Entrez	10266

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000253796, ENST00000587142, ENST00000588576, ENST00000588928, ENST00000589683, ENST00000591972, ENST00000904024

RefSeq mRNA: 1 — MANE Select: NM_005854 NM_005854

CCDS: CCDS11437

Canonical transcript exons

ENST00000253796 — 4 exons

Exon	Start	End
ENSE00001299889	42761227	42761358
ENSE00002762898	42762597	42763041
ENSE00003661168	42762355	42762463
ENSE00003688721	42761834	42761899

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 99.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4058 / max 747.7673, expressed in 942 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160989	6.3028	507
160986	3.6650	848
160987	0.6069	286
160984	0.6064	253
160988	0.5271	260
160985	0.4003	192
160990	0.2972	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.12	gold quality
mucosa of stomach	UBERON:0001199	97.69	gold quality
omental fat pad	UBERON:0010414	97.67	gold quality
apex of heart	UBERON:0002098	97.62	gold quality
peritoneum	UBERON:0002358	97.58	gold quality
upper lobe of left lung	UBERON:0008952	97.48	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.94	gold quality
tibial nerve	UBERON:0001323	96.50	gold quality
endocervix	UBERON:0000458	96.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.44	gold quality
upper lobe of lung	UBERON:0008948	96.26	gold quality
right coronary artery	UBERON:0001625	95.68	gold quality
left uterine tube	UBERON:0001303	95.42	gold quality
right lobe of thyroid gland	UBERON:0001119	95.37	gold quality
right atrium auricular region	UBERON:0006631	95.01	gold quality
body of uterus	UBERON:0009853	94.39	gold quality
left lobe of thyroid gland	UBERON:0001120	94.12	gold quality
ectocervix	UBERON:0012249	94.02	gold quality
cardiac atrium	UBERON:0002081	93.89	gold quality
gall bladder	UBERON:0002110	93.83	gold quality
metanephros cortex	UBERON:0010533	93.82	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.47	gold quality
heart left ventricle	UBERON:0002084	93.42	gold quality
adipose tissue	UBERON:0001013	93.40	gold quality
left coronary artery	UBERON:0001626	93.10	gold quality
skin of leg	UBERON:0001511	93.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.01	gold quality
cardiac ventricle	UBERON:0002082	92.94	gold quality
lower esophagus	UBERON:0013473	92.92	gold quality

Single-cell (SCXA)

Detected in 36 experiment(s), a significant marker in 35.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	3550.34
E-MTAB-6653	yes	3451.61
E-MTAB-10042	yes	3414.29
E-MTAB-8221	yes	3307.32
E-MTAB-9906	yes	3176.78
E-MTAB-7407	yes	2219.90
E-CURD-126	yes	2201.98
E-MTAB-6701	yes	2145.63
E-MTAB-10662	yes	1900.57
E-HCAD-11	yes	1830.07
E-HCAD-10	yes	1765.19
E-MTAB-6308	yes	1715.96
E-GEOD-124472	yes	1705.27
E-MTAB-8410	yes	1656.45
E-HCAD-24	yes	1512.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CDH5	Activation
CLDN1	Activation
CLDN5	Activation
COL4A1	Activation
NOS3	Activation
VEGFA	Activation

miRNA regulators (miRDB)

25 targeting RAMP2, 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-12136	99.98	72.81	5713
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-4450	98.26	68.35	725
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-4693-3P	95.23	65.92	735
HSA-MIR-12115	94.19	66.37	738

Literature-anchored findings (GeneRIF, showing 28)

• results show the presence of calcitonin receptor-like receptor and receptor activity-modifying proteins in middle meningeal, middle cerebral, pial, and superficial temporal vessels (PMID:11973435)
• Co-expression of calcitonin receptors (CT) lacking a portion of domain 1 with receptor activity-modifying protein (RAMP) 1, 2, or 3 appears to produce functional CT-(8-32)-sensitive adrenomedullin receptors. (PMID:12565884)
• TNF-alpha induced time- and dose-dependent decreases in the expression of RAMP2 mRNA in cultured human coronary artery smooth muscle cells , thereby diminishing AM-evoked cAMP production (PMID:15245870)
• Data found that expressions of RAMP1, RAMP2 and RAMP3 mRNAs increased with the worsening of heart function, but the expressions of RAMP1 and RAMP2 mRNA decreased at level IV of heart failure. (PMID:15300632)
• adrenomedullin receptors are comprised of RAMP2 and calcitonin receptor-like receptor. (PMID:15613468)
• the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization (PMID:16410241)
• This study reveals important functionality of the RAMP C-terminal domain and identifies key differences in the role of the RAMP C terminus for calcitonin receptor versus calcitonin receptor-like receptor-based receptors. (PMID:16912219)
• RAMP2 is silenced by promoter hypermethylation in lung cancer (PMID:17671114)
• Identification of RAMP2 residues for adrenomedullin receptors are reported. (PMID:18593822)
• The His residues of hRAMP2 and -3 differentially govern adrenomedullin receptor function. (PMID:18835256)
• findings provided no significant linkage or association of adrenomedullin and CRLR-RAMP-2 genes with rheumatoid arthritis in the studied trio families (PMID:19210874)
• the hCRLR C-tail is crucial for adrenomedullin-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling. (PMID:20074556)
• The CRLR-RAMP2 interactions were confirmed for the full-length proteins on the cell surface by site-specific photo-crosslinking. (PMID:22102369)
• RAMP2 gene expression increases with gestational age development in the fetal lung. (PMID:24169318)
• Data suggest isoforms of RAMP modulate accessibility of peptides to residues situated on CALCRL (calcitonin receptor-like receptor) N-terminal domain; RAMP3/RAMP2/RAMP1 appear to alter accessibility of specific residues at CALCRL-RAMP interface. (PMID:24199627)
• Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. (PMID:24505304)
• the AM system is widely expressed in human thymus from newborns; both AM1 receptor components CLR and RAMP2, but not RAMP3, are not associated with the plasma membrane of TECs and thymocytes but are located intracellularly, notably in the nucleus (PMID:24831942)
• Data suggest that ligand binding of a G protein-coupled receptor (GPCR) may inform drug development targeting calcitonin receptor-like receptor (CLR):receptor activity-modifying proteins RAMP1/2 complexes. (PMID:25982113)
• This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. (PMID:26198634)
• interaction of RAMP2 or RAMP3 with CLR induces conformational variation in the juxtamembrane region, yielding distinct binding pockets, probably via an allosteric mechanism. (PMID:27013657)
• This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities. (PMID:28586439)
• Data suggest that a single GlcNAc residue at CTR N130 (asparagine 130) is responsible for enhanced affinity of calcitonin for CTR ECD; the same appears to apply for enhanced affinity of amylin for RAMP2-CTR ECD. [GlcNAc = N-acetylglucosamine; CTR = calcitonin receptor; ECD = extracellular domain; RAMP2 = receptor (calcitonin) activity modifying protein 2]. (PMID:28614667)
• Single nucleotide polymorphism of RAMP2 is associated with Stroke. (PMID:28904253)
• Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context (PMID:30826286)
• Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. (PMID:31150417)
• Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration. (PMID:33385343)
• Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling. (PMID:34271220)
• RAMP2-AS1 stabilized RAPM2 mRNA through TIA1 to inhibit the progression of non-small cell lung cancer. (PMID:38279501)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ramp2	ENSDARG00000037895
mus_musculus	Ramp2	ENSMUSG00000001240
rattus_norvegicus	Ramp2	ENSRNOG00000085964

Paralogs (2): RAMP3 (ENSG00000122679), RAMP1 (ENSG00000132329)

Protein

Protein identifiers

Receptor activity-modifying protein 2 — O60895 (reviewed: O60895)

Alternative names: Calcitonin-receptor-like receptor activity-modifying protein 2

All UniProt accessions (4): O60895, K7EKQ3, K7ENJ8, K7EPN3

UniProt curated annotations — full annotation on UniProt →

Function. Accessory protein that interacts with and modulates the function of G-protein coupled receptors including calcitonin gene-related peptide type 1 receptor (CALCRL) and calcitonin receptor (CALCR). Required for the transport of CALCRL to the plasma membrane. Together with CALCRL, form a receptor complex for adrenomedullin/ADM. Together with CALCR, act as a receptor complex for calcitonin/CT/CALC. Together with CALCR, also act as a receptor complex for amylin/IAPP.

Subunit / interactions. Heterodimer of CALCRL and RAMP2; the interaction forms the receptor complex for adrenomedullin/ADM. Heterodimer of CALCR and RAMP2; interaction forms the AMYR2 receptor complex for calcitonin/CALC and amylin/IAPP.

Subcellular location. Cell membrane.

Tissue specificity. Strongly expressed in lung, breast, immune system and fetal tissues.

Similarity. Belongs to the RAMP family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60895-1	1	yes
O60895-2	2

RefSeq proteins (1): NP_005845* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006985	RAMP	Family
IPR038126	RAMP_sf	Homologous_superfamily

Pfam: PF04901

UniProt features (20 total): helix 6, sequence conflict 2, topological domain 2, disulfide bond 2, signal peptide 1, chain 1, strand 1, turn 1, transmembrane region 1, site 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4RWF	X-RAY DIFFRACTION	1.76
6V2E	X-RAY DIFFRACTION	1.83
3AQE	X-RAY DIFFRACTION	2
2XVT	X-RAY DIFFRACTION	2.05
7TYX	ELECTRON MICROSCOPY	2.55
3AQF	X-RAY DIFFRACTION	2.6
9BQ3	ELECTRON MICROSCOPY	2.8
6UUN	ELECTRON MICROSCOPY	3
7TYY	ELECTRON MICROSCOPY	3
7TYH	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60895-F1	82.19	0.60

Antibody-complex structures (SAbDab): 4 — 6UUN, 7TYH, 7TYX, 7TYY

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): 139 (required for calcrl interaction)

Disulfide bonds (2): 68–99, 84–131

Glycosylation sites (1): 130

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-419812	Calcitonin-like ligand receptors
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 263 (showing top): RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOCC_CELL_SURFACE, AP4_Q6, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, GOBP_VASCULAR_ASSOCIATED_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_VESICLE_MEDIATED_TRANSPORT, DARWICHE_PAPILLOMA_PROGRESSION_RISK, CHANDRAN_METASTASIS_DN

GO Biological Process (26): angiogenesis (GO:0001525), vasculogenesis (GO:0001570), sprouting angiogenesis (GO:0002040), calcium ion transport (GO:0006816), intracellular protein transport (GO:0006886), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), heart development (GO:0007507), regulation of blood pressure (GO:0008217), regulation of G protein-coupled receptor signaling pathway (GO:0008277), positive regulation of gene expression (GO:0010628), protein transport (GO:0015031), receptor internalization (GO:0031623), cellular response to hormone stimulus (GO:0032870), adherens junction assembly (GO:0034333), cellular response to vascular endothelial growth factor stimulus (GO:0035924), negative regulation of vascular permeability (GO:0043116), positive regulation of angiogenesis (GO:0045766), bicellular tight junction assembly (GO:0070830), basement membrane assembly (GO:0070831), protein localization to plasma membrane (GO:0072659), vascular associated smooth muscle cell development (GO:0097084), amylin receptor 2 signaling pathway (GO:0150060), adrenomedullin receptor signaling pathway (GO:1990410), negative regulation of endothelial cell apoptotic process (GO:2000352), positive regulation of vasculogenesis (GO:2001214)

GO Molecular Function (4): adrenomedullin receptor activity (GO:0001605), coreceptor activity (GO:0015026), adrenomedullin binding (GO:1990409), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), lysosome (GO:0005764), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), cell surface (GO:0009986), signaling receptor complex (GO:0043235), adrenomedullin receptor complex (GO:1903143), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
blood vessel morphogenesis	2
angiogenesis	2
intracellular protein localization	2
membrane	2
anatomical structure formation involved in morphogenesis	1
cell differentiation	1
metal ion transport	1
protein transport	1
intracellular transport	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
animal organ development	1
circulatory system development	1
blood circulation	1
regulation of biological quality	1
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
transport	1
establishment of protein localization	1
receptor-mediated endocytosis	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
cell-cell junction assembly	1
adherens junction organization	1
cellular response to growth factor stimulus	1
regulation of vascular permeability	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
apical junction assembly	1
tight junction assembly	1
basement membrane organization	1
extracellular matrix assembly	1
calcitonin family receptor activity	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAMP2	ADM	P35318	999
RAMP2	CALCRL	Q16602	999
RAMP2	CALCR	P30988	994
RAMP2	IAPP	P10997	949
RAMP2	VIPR1	P32241	941
RAMP2	CALCA	P01258	925
RAMP2	CALCB	P10092	907
RAMP2	RAMP3	O60896	897
RAMP2	ADM2	Q7Z4H4	880
RAMP2	VIPR2	P41587	733
RAMP2	RAMP1	O60894	653
RAMP2	PTH1R	Q03431	589
RAMP2	ADGRF5	Q8IZF2	581
RAMP2	VIP	P01282	544
RAMP2	ACKR5	O15218	507

IntAct

436 interactions, top by confidence:

A	B	Type	Score
RAMP2	CALCRL	psi-mi:“MI:0915”(physical association)	0.760
CALCRL	RAMP2	psi-mi:“MI:0915”(physical association)	0.760
RAMP2	LCN2	psi-mi:“MI:0915”(physical association)	0.560
RAMP2	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
ADORA1	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
CXCR5	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
CYSLTR2	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
GABBR1	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	GLP1R	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	GPRC5A	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	NPFFR2	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	ADORA1	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	CXCR5	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	CYSLTR2	psi-mi:“MI:0915”(physical association)	0.470
FZD4	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	GABBR1	psi-mi:“MI:0915”(physical association)	0.470
ACKR3	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
ADGRG3	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
ADGRG5	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
ADORA2B	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
ADRB1	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	ADRB3	psi-mi:“MI:0915”(physical association)	0.400
AGTR2	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	AVPR1A	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	BDKRB1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	C5AR1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	C5AR2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	CALCR	psi-mi:“MI:0915”(physical association)	0.400
CCKAR	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	CCKBR	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (75): RAMP2 (Reconstituted Complex), RAMP2 (Affinity Capture-MS), CIDEB (Two-hybrid), LCN2 (Two-hybrid), C3orf33 (Affinity Capture-MS), STK39 (Affinity Capture-MS), AGPAT5 (Affinity Capture-MS), POLG (Affinity Capture-MS), LOC81691 (Affinity Capture-MS), SLC25A40 (Affinity Capture-MS), RDH13 (Affinity Capture-MS), SLC10A7 (Affinity Capture-MS), CDYL (Affinity Capture-MS), CDC6 (Affinity Capture-MS), FAR2 (Affinity Capture-MS)

ESM2 similar proteins: A7MBM2, E9PY61, O00391, O08542, O60894, O60895, O76095, O77049, O88824, P52798, Q15904, Q16586, Q5Q0T9, Q5RJL6, Q641Q3, Q6IUU3, Q6P5F7, Q6PRD1, Q6UWJ8, Q6ZVN8, Q6ZVW7, Q7TQ32, Q80YF6, Q864V4, Q867C0, Q86WC4, Q8BGT0, Q8BH06, Q8BND5, Q8C1Q4, Q8K4C2, Q8N271, Q8N7M5, Q8NAC3, Q8R4C4, Q8R4C5, Q8R4C6, Q8VE43, Q91ZV8, Q96F46

Diamond homologs: O60895, Q7YS88, Q8R4C4, Q8R4C5, Q9JHJ1, Q9JJ73, Q9WUP0, Q9WUP1, O60894, O60896, Q867C0, Q8R4C6, Q9JJ74, Q9WTJ5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RAMP2	“form complex”	“Amylin receptor 2 complex”	binding
RAMP2	“form complex”	“Adrenomedullin receptor AM1 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 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
Amine ligand-binding receptors	18	45.5×	1e-25
Class A/1 (Rhodopsin-like receptors)	62	33.6×	4e-81
GPCR ligand binding	54	25.3×	6e-62
Peptide ligand-binding receptors	44	23.8×	1e-48
G alpha (q) signalling events	46	19.3×	2e-46
Chemokine receptors bind chemokines	13	17.8×	3e-12
G alpha (i) signalling events	59	16.8×	9e-57
GPCR downstream signalling	51	16.2×	1e-47

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	26	50.7×	8e-37
complement receptor mediated signaling pathway	7	49.1×	2e-09
activation of adenylate cyclase activity	7	49.1×	2e-09
dendritic cell chemotaxis	7	43.4×	6e-09
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	30	41.0×	4e-39
phospholipase C-activating G protein-coupled receptor signaling pathway	40	32.9×	3e-48
positive regulation of cytosolic calcium ion concentration	43	31.4×	5e-51
adenylate cyclase-activating G protein-coupled receptor signaling pathway	39	27.6×	1e-43

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

563 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42761354:GGGCG:G	donor_gain	1.0000
17:42761355:GGCGG:G	donor_gain	1.0000
17:42761356:GCG:G	donor_gain	1.0000
17:42761832:A:AG	acceptor_gain	1.0000
17:42761833:G:GG	acceptor_gain	1.0000
17:42761833:GCT:G	acceptor_gain	1.0000
17:42761900:G:GC	donor_loss	1.0000
17:42761901:T:A	donor_loss	1.0000
17:42762353:AGGG:A	acceptor_gain	1.0000
17:42762353:AGGGG:A	acceptor_gain	1.0000
17:42762354:GGGG:G	acceptor_gain	1.0000
17:42762354:GGGGG:G	acceptor_gain	1.0000
17:42761355:GGCG:G	donor_gain	0.9900
17:42761356:GCGG:G	donor_gain	0.9900
17:42761356:GCGGT:G	donor_loss	0.9900
17:42761359:G:GG	donor_gain	0.9900
17:42761359:GT:G	donor_loss	0.9900
17:42761360:T:TC	donor_loss	0.9900
17:42761361:GAGC:G	donor_loss	0.9900
17:42761410:G:T	donor_gain	0.9900
17:42761829:CACAG:C	acceptor_loss	0.9900
17:42761830:ACAGC:A	acceptor_loss	0.9900
17:42761831:CAG:C	acceptor_loss	0.9900
17:42761832:A:T	acceptor_loss	0.9900
17:42761833:GC:G	acceptor_gain	0.9900
17:42761833:GCTGT:G	acceptor_gain	0.9900
17:42761896:GAAG:G	donor_gain	0.9900
17:42762349:CTACA:C	acceptor_loss	0.9900
17:42762350:TACAG:T	acceptor_loss	0.9900
17:42762352:CA:C	acceptor_loss	0.9900

AlphaMissense

1141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42762449:G:C	W86C	0.997
17:42762449:G:T	W86C	0.997
17:42762707:T:G	F128C	0.996
17:42762655:T:C	F111L	0.995
17:42762657:C:A	F111L	0.995
17:42762657:C:G	F111L	0.995
17:42762706:T:C	F128L	0.995
17:42762708:T:A	F128L	0.995
17:42762708:T:G	F128L	0.995
17:42762707:T:C	F128S	0.992
17:42762787:T:C	C155R	0.992
17:42762441:T:A	C84S	0.991
17:42762442:G:C	C84S	0.991
17:42762656:T:G	F111C	0.991
17:42762715:T:A	C131S	0.987
17:42762716:G:C	C131S	0.987
17:42762717:C:G	C131W	0.985
17:42762716:G:A	C131Y	0.984
17:42762442:G:A	C84Y	0.983
17:42762694:C:G	H124D	0.982
17:42762623:T:C	L100P	0.981
17:42762715:T:C	C131R	0.981
17:42762782:C:G	P153R	0.979
17:42762393:T:A	C68S	0.978
17:42762394:G:A	C68Y	0.978
17:42762394:G:C	C68S	0.978
17:42762447:T:A	W86R	0.978
17:42762447:T:C	W86R	0.978
17:42762716:G:T	C131F	0.978
17:42762797:C:G	P158R	0.978

dbSNP variants (sampled 300 via entrez): RS1000250435 (17:42762272 C>G,T), RS1003471186 (17:42761167 G>A,C), RS1004091198 (17:42759242 T>C), RS1005343641 (17:42761628 G>A), RS1006294113 (17:42760837 T>C), RS1006698799 (17:42760950 C>G,T), RS1007015458 (17:42763279 G>A,T), RS1007296237 (17:42762502 G>A), RS1010307377 (17:42763203 CT>C), RS1011002861 (17:42760021 C>T), RS1011058104 (17:42760162 T>C), RS1012008614 (17:42761454 G>A), RS1012098726 (17:42761289 G>A), RS1012589996 (17:42761024 G>C), RS1012612670 (17:42762183 A>C,G)

Disease associations

OMIM: gene MIM:605154 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
open-angle glaucoma	Moderate	Autosomal dominant

Mondo (1): open-angle glaucoma (MONDO:0005338)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006629_9	Pulse pressure	2.000000e-16
GCST90020024_520	A body shape index	3.000000e-09
GCST90020025_1445	Waist-to-hip ratio adjusted for BMI	5.000000e-14
GCST90020025_1446	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90020027_417	Waist-hip index	5.000000e-14
GCST90020027_418	Waist-hip index	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005902	Glaucoma, Open-Angle	C11.525.381.407

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2109232 (PROTEIN COMPLEX), CHEMBL2364173 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 883 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2103758	PRAMLINTIDE	4	883
CHEMBL4802169	CAGRILINTIDE	3

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.37	EC50	0.04266	nM	CAGRILINTIDE
10.19	EC50	0.06457	nM	PRAMLINTIDE
9.74	EC50	0.182	nM	CHEMBL5567377

PubChem BioAssay actives

3 with measured affinity, of 13 total; 3 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
(4S)-4-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S,19S,22R)-22-amino-16-(2-amino-2-oxoethyl)-7-[(1R)-1-hydroxyethyl]-10,19-bis(hydroxymethyl)-13-(2-methylpropyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S,3R)-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S,3R)-1-[[(2S)-4-amino-1-[[(2S,3R)-1-[[2-[[(2S)-1-[[2-[[(2S,3R)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	2085718: Agonist activity at human AMY2R complex of CTR/RAMP2 transduced in human HeLa cells by cAMP assay	ec50	<0.0001	uM
Pramlintide	2085718: Agonist activity at human AMY2R complex of CTR/RAMP2 transduced in human HeLa cells by cAMP assay	ec50	0.0001	uM
(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-4-amino-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S,3S)-1-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-4-amino-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1,4-dioxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S,19R)-16-(2-amino-2-oxoethyl)-19-[[(2S)-2,6-diaminohexanoyl]amino]-7,13-bis[(1R)-1-hydroxyethyl]-10-methyl-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-4-oxobutanoic acid	2085718: Agonist activity at human AMY2R complex of CTR/RAMP2 transduced in human HeLa cells by cAMP assay	ec50	0.0002	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
OTX015	decreases expression	1
bisphenol A	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
3-nitrobenzanthrone	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects methylation	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Deferoxamine	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Lead	affects expression	1
Methotrexate	decreases expression	1
Oxygen	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Endocannabinoids	affects binding, decreases reaction, increases activity	1

ChEMBL screening assays

7 unique, capped per target: 4 functional, 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2040044	Binding	Displacement of [125I]adrenomedullin from human AM1 receptor expressed in HEK293 cells	MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats. — Bioorg Med Chem Lett
CHEMBL4425538	Functional	Agonist activity at eYFP-tagged CLR/eCFP-tagged RAMP2-derived AM1 receptor (unknown origin) expressed in HEK293 cells assessed as cAMP accumulation after 3 hrs by ONE-Glo substrate-based luminescence assay	Adrenomedullin 2.0: Adjusting Key Levers for Metabolic Stability. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 spontaneously immortalized cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H396	CHO-K1/AM1	Spontaneously immortalized cell line	Female
CVCL_H400	CHO-K1/AMY2/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KA09	CHO-K1/Galpha15/AMY2	Spontaneously immortalized cell line	Female
CVCL_KW49	PathHunter CHO-K1 CALCRL-RAMP2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_KW51	PathHunter CHO-K1 CALCR-RAMP2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_TI45	HAP1 RAMP2 (-) 1	Cancer cell line	Male
CVCL_TI46	HAP1 RAMP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00047606	PHASE4	TERMINATED	Phase 4 Study Comparing IOP Lowering in OAG or OH in Caucasian or Japanese Subjects C-02-32
NCT00273429	PHASE4	COMPLETED	Cosopt Versus Xalatan
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT00273455	PHASE4	COMPLETED	Lumigan Versus Cosopt
NCT00273481	PHASE4	COMPLETED	Cosopt Versus Xalacom
NCT00300079	PHASE4	COMPLETED	Study of the Intraocular Pressure (IOP)-Lowering Efficacy of Azopt 1.0% Compared to Timolol 0.5% in Patients With Glaucoma or Ocular Hypertension
NCT00304785	PHASE4	COMPLETED	Latanoprost Versus Fotil
NCT00308945	PHASE4	COMPLETED	Influence of Prostaglandins on Ocular Blood Flow in Glaucoma Patients
NCT00326014	PHASE4	COMPLETED	A Study of the Trabecular Micro-Bypass Stent in Combination With Cataract Surgery in Open Angle Glaucoma Subjects.
NCT00326040	PHASE4	COMPLETED	A Study of the Glaukos Trabecular Micro-Bypass Stent in Refractory Open Angle Glaucoma Subjects
NCT00326079	PHASE4	UNKNOWN	A Study of the Glaukos Trabecular Micro-bypass Stent in Open Angle Glaucoma Subjects 1 Stent Versus 2
NCT00330577	PHASE4	COMPLETED	24-Hour Intraocular Pressure (IOP) And Blood Pressure Control In Glaucoma And Ocular Hypertension Patients
NCT00372827	PHASE4	COMPLETED	Study of Brinzolamide and Timolol When Added to Travoprost in Primary Open-angle Glaucoma or Ocular Hypertension
NCT00397241	PHASE4	COMPLETED	24-hour Study of Dorzolamide/Timolol and Latanoprost/Timolol Fixed Combinations
NCT00457795	PHASE4	COMPLETED	24-hour IOP-lowering Effect of Brimonidine 0.1%
NCT00471068	PHASE4	TERMINATED	Study of Travatan and Cosopt in Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00508469	PHASE4	COMPLETED	Adherence Assessment With Travalert Dosing Aid
NCT00527592	PHASE4	COMPLETED	A Single Dose Comfort Comparison of Travatan Z in One Eye Versus Xalatan in the Opposite Eye in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00538590	PHASE4	COMPLETED	Ologen Collagen Matrix Safety and Effective Comparison With Mitomycin-C(MMC) in Glaucoma Surgery
NCT00539526	PHASE4	COMPLETED	Evaluation of Hyperemia With the Use of Ocular Prostaglandin Analogues
NCT00545064	PHASE4	COMPLETED	Dry Eye Study With Cosopt® Over 8 Weeks in Patients With Open-Angle Glaucoma or Ocular Hypertension (0507A-152)(COMPLETED)
NCT00675207	PHASE4	COMPLETED	Comparison of Brimonidine Purite, Dorzolamide, and Brinzolamide as Adjunctive Therapy to Prostaglandin Analogs
NCT00698945	PHASE4	COMPLETED	Comparison of Istalol™ 0.5% QD (Timolol Maleate/Sorbitol Complex, ISTA Pharmaceutical) to Brimonidine Tartrate 0.1% BID as Adjunctive Therapy to Latanoprost 0.005% in Adults With Ocular Hypertension (OHT) or Open-Angle Glaucoma (OAG)
NCT00759239	PHASE4	COMPLETED	Phase IV Randomised Double-masked Clinical Trial: Assessing Morning Versus Evening Dosing of a Fixed Dose Combination of Travoprost 0.004% / Timolol Maleate 0.5% in Patients With Primary Open-angle Glaucoma or Ocular Hypertension
NCT00798759	PHASE4	COMPLETED	Examination of Ocular Surface Effects With Administration of Travatan Z and XALATAN
NCT00803803	PHASE4	COMPLETED	Dose, Effects and Characteristics of Pilocarpine
NCT00822055	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00822081	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00828906	PHASE4	COMPLETED	DuoTrav® Eye Drops As Replacement Therapy Program
NCT00887029	PHASE4	COMPLETED	A 12 Week Comparison of DuoTrav and Xalacom in Open-Angle Glaucoma
NCT00941525	PHASE4	COMPLETED	Central Corneal Thickness and 24-hour Fluctuation of Intraocular Pressure
NCT01055366	PHASE4	COMPLETED	ELAZOP Switching Study in Korea
NCT01162603	PHASE4	COMPLETED	Latanoprost Versus Tafluprost: 24-hour Intraocular Pressure (IOP)
NCT01327599	PHASE4	COMPLETED	Efficacy of Changing to DUOTRAV® From Prior Therapy
NCT01340014	PHASE4	COMPLETED	Patient Preference Comparison of AZARGA Versus COSOPT
NCT01369771	PHASE4	COMPLETED	The Effects of Preservative-free Prostaglandin Eye Drops in Sign and Symptoms on the Eyes of Patients With Glaucoma
NCT01415401	PHASE4	COMPLETED	Efficacy and Tolerability of AZARGA® as Replacement Therapy in Patients on COMBIGAN® Therapy in Canada
NCT01443988	PHASE4	COMPLETED	Subjects With Open-angle Glaucoma, Pseudoexfoliative Glaucoma, or Ocular Hypertension Naïve to Medical and Surgical Therapy, Treated With Two Trabecular Micro-bypass Stents (iStent)or Travoprost
NCT01444040	PHASE4	COMPLETED	Subjects With Open-angle Glaucoma, Pseudoexfoliative Glaucoma, or Ocular Hypertension Naïve to Medical and Surgical Therapy, Treated With Two Trabecular Micro-bypass Stents (iStent Inject) or Travoprost
NCT01464424	PHASE4	COMPLETED	Assessment of Intraocular Pressure (IOP) Control in Subjects With Open-Angle Glaucoma or Ocular Hypertension Treated With Travoprost 0.004% (TRAVATAN® Z) or Bimatoprost 0.01% (LUMIGAN®)