KDELR2

Summary

KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2, HGNC:6305) is a protein-coding gene on chromosome 7p22.1, encoding ER lumen protein-retaining receptor 2 (P33947). Membrane receptor that binds the K-D-E-L sequence motif in the C-terminal part of endoplasmic reticulum resident proteins and maintains their localization in that compartment by participating to their vesicle-mediated recycling back from the Golgi.

Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells, and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes, and binds the tetrapeptide-containing protein, and returns it to the ER. In yeast, the sorting receptor encoded by a single gene, ERD2, is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. KDELR2 was the second member of the family to be identified, and it encodes a protein which is 83% identical to the KDELR1 gene product. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 11014 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta, type 21 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 48 total — 4 pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• MANE Select transcript: NM_006854

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6305
Approved symbol	KDELR2
Name	KDEL endoplasmic reticulum protein retention receptor 2
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	ELP-1, ERD2.2
Ensembl gene	ENSG00000136240
Ensembl biotype	protein_coding
OMIM	609024
Entrez	11014

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000258739, ENST00000382267, ENST00000454368, ENST00000462052, ENST00000463747, ENST00000490996, ENST00000854602, ENST00000854603, ENST00000854604, ENST00000854605, ENST00000854606, ENST00000958354

RefSeq mRNA: 2 — MANE Select: NM_006854 NM_001100603, NM_006854

CCDS: CCDS43550, CCDS5351

Canonical transcript exons

ENST00000258739 — 5 exons

Exon	Start	End
ENSE00000923872	6469596	6469754
ENSE00001557095	6483967	6484152
ENSE00001893172	6461089	6463175
ENSE00003513677	6474184	6474284
ENSE00003531130	6466071	6466323

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 267.7552 / max 1965.4589, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82654	267.7552	1827
82653	3.7652	1147

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.25	gold quality
tibia	UBERON:0000979	99.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.68	gold quality
calcaneal tendon	UBERON:0003701	98.67	gold quality
rectum	UBERON:0001052	98.57	gold quality
colonic mucosa	UBERON:0000317	98.44	gold quality
pylorus	UBERON:0001166	98.41	gold quality
smooth muscle tissue	UBERON:0001135	98.39	gold quality
cartilage tissue	UBERON:0002418	98.35	gold quality
tendon	UBERON:0000043	98.23	gold quality
jejunal mucosa	UBERON:0000399	98.21	gold quality
pericardium	UBERON:0002407	98.17	gold quality
tendon of biceps brachii	UBERON:0008188	98.15	gold quality
type B pancreatic cell	CL:0000169	98.07	gold quality
right lobe of liver	UBERON:0001114	98.06	gold quality
islet of Langerhans	UBERON:0000006	98.04	gold quality
endometrium	UBERON:0001295	98.04	gold quality
placenta	UBERON:0001987	97.98	gold quality
body of pancreas	UBERON:0001150	97.94	gold quality
parotid gland	UBERON:0001831	97.90	gold quality
liver	UBERON:0002107	97.90	gold quality
gall bladder	UBERON:0002110	97.89	gold quality
duodenum	UBERON:0002114	97.89	gold quality
ascending aorta	UBERON:0001496	97.84	gold quality
thoracic aorta	UBERON:0001515	97.83	gold quality
periodontal ligament	UBERON:0008266	97.82	gold quality
mucosa of transverse colon	UBERON:0004991	97.77	gold quality
trachea	UBERON:0003126	97.73	gold quality
cardia of stomach	UBERON:0001162	97.65	gold quality
adult organism	UBERON:0007023	97.58	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	95.26
E-MTAB-9467	yes	56.95
E-HCAD-4	yes	52.27
E-HCAD-1	yes	48.59
E-CURD-122	yes	43.03
E-CURD-46	yes	39.28
E-HCAD-5	yes	37.38
E-HCAD-10	yes	28.35
E-CURD-112	yes	15.82
E-HCAD-9	yes	15.03
E-MTAB-10042	yes	8.36
E-MTAB-7303	no	1246.72
E-GEOD-125970	no	17.82
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting KDELR2, 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-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-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-8087	99.90	69.55	1351
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6844	99.82	70.69	2423

Literature-anchored findings (GeneRIF, showing 10)

• A Golgi-based KDELR-dependent signalling pathway controls invadopodia-dependent extracellular matrix degradation. (PMID:25682866)
• Our data indicate that KDELR2 competes with measles virus (MV) envelope proteins for binding to calnexin and GRP78/Bip, and that this interaction limits the availability of the chaperones for MV proteins, causing the reduction of virus spread and titers. (PMID:30621148)
• show that Golgi-based, KDEL receptor-dependent signalling promotes lysosome repositioning to the perinuclear area, involving a complex process intertwined to autophagy, lipid-droplet turnover and Golgi-mediated secretion. (PMID:30760704)
• KDELR2 is a target gene downstream of HIF1-alpha driving the malignancy of glioblastoma. (PMID:31342232)
• KDELR2 is an unfavorable prognostic biomarker and regulates CCND1 to promote tumor progression in glioma. (PMID:32534703)
• Cell-type-specific differences in KDEL receptor clustering in mammalian cells. (PMID:32645101)
• Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. (PMID:33053334)
• Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. (PMID:33964184)
• KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression. (PMID:34146461)
• KDELR2 is necessary for chronic obstructive pulmonary disease airway Mucin5AC hypersecretion via an IRE1alpha/XBP-1s-dependent mechanism. (PMID:39365189)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdelr2a	ENSDARG00000005254
danio_rerio	kdelr2b	ENSDARG00000037361
mus_musculus	Kdelr2	ENSMUSG00000079111
rattus_norvegicus	Kdelr2	ENSRNOG00000001083
drosophila_melanogaster	KdelR	FBGN0267330
caenorhabditis_elegans		WBGENE00001331
caenorhabditis_elegans		WBGENE00016195

Paralogs (2): KDELR3 (ENSG00000100196), KDELR1 (ENSG00000105438)

Protein

Protein identifiers

ER lumen protein-retaining receptor 2 — P33947 (reviewed: P33947)

Alternative names: ERD2-like protein 1, KDEL endoplasmic reticulum protein retention receptor 2

All UniProt accessions (2): P33947, H7BYF7

UniProt curated annotations — full annotation on UniProt →

Function. Membrane receptor that binds the K-D-E-L sequence motif in the C-terminal part of endoplasmic reticulum resident proteins and maintains their localization in that compartment by participating to their vesicle-mediated recycling back from the Golgi. Binding is pH dependent, and is optimal at pH 5-5.4.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Cytoplasmic vesicle. COPI-coated vesicle membrane.

Disease relevance. Osteogenesis imperfecta 21 (OI21) [MIM:619131] An autosomal recessive form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI21 is a progressively deforming form characterized by multiple fractures appearing at birth or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds the C-terminal sequence motif K-D-E-L in a hydrophilic cavity between the transmembrane domains. This triggers a conformation change that exposes a Lys-rich patch on the cytosolic surface of the protein. This patch mediates recycling from the Golgi to the endoplasmic reticulum, probably via COPI vesicles.

Similarity. Belongs to the ERD2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P33947-1	1	yes
P33947-2	2

RefSeq proteins (2): NP_001094073, NP_006845* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000133	ER_ret_rcpt	Family

Pfam: PF00810

UniProt features (30 total): topological domain 8, transmembrane region 7, sequence variant 5, site 4, region of interest 3, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33947-F1	93.12	0.84

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 (4): 5 (interaction with the k-d-e-l motif on target proteins); 54 (interaction with the k-d-e-l motif on target proteins); 117 (interaction with the k-d-e-l motif on target proteins); 193 (important for recycling of cargo proteins with the sequence motif k-d-e-l from the golgi to the endoplasmic reticulum)

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic

MSigDB gene sets: 286 (showing top): KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, chr7p22, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, GOBP_MAINTENANCE_OF_LOCATION, GOCC_COATED_VESICLE, GOBP_MAINTENANCE_OF_PROTEIN_LOCALIZATION_IN_ORGANELLE, WTGAAAT_UNKNOWN, RHODES_CANCER_META_SIGNATURE, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOCC_GOLGI_ASSOCIATED_VESICLE

GO Biological Process (5): protein retention in ER lumen (GO:0006621), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), protein transport (GO:0015031), maintenance of protein localization in endoplasmic reticulum (GO:0035437), vesicle-mediated transport (GO:0016192)

GO Molecular Function (2): KDEL sequence binding (GO:0005046), ER lumen protein retrieval receptor activity (GO:0046923)

GO Cellular Component (9): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cis-Golgi network (GO:0005801), membrane (GO:0016020), transport vesicle (GO:0030133), COPI-coated vesicle membrane (GO:0030663), Golgi apparatus (GO:0005794), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
endomembrane system	3
intracellular membrane-bounded organelle	3
transport	2
Golgi apparatus	2
maintenance of protein localization in endoplasmic reticulum	1
Golgi vesicle transport	1
intracellular protein localization	1
establishment of protein localization	1
endoplasmic reticulum	1
protein localization to endoplasmic reticulum	1
maintenance of protein localization in organelle	1
cellular process	1
ER lumen protein retrieval receptor activity	1
signal sequence receptor activity	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cytoplasmic vesicle	1
COPI-coated vesicle	1
Golgi-associated vesicle membrane	1
coated vesicle membrane	1
intracellular vesicle	1

Protein interactions and networks

STRING

992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDELR2	COPB1	P53618	821
KDELR2	LRIG3	Q6UXM1	731
KDELR2	GOLPH3	Q9H4A6	692
KDELR2	SLC34A2	O95436	656
KDELR2	RET	P07949	638
KDELR2	ROS1	P08922	628
KDELR2	GOPC	Q9HD26	585
KDELR2	GRID2IP	A4D2P6	583
KDELR2	TPD52L1	Q16890	572
KDELR2	SDC4	P31431	570
KDELR2	TPM3	P06753	548
KDELR2	TMEM106B	Q9NUM4	507
KDELR2	LIMA1	Q9UHB6	507
KDELR2	CD74	P04233	482
KDELR2	EZR	P15311	475

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
PARP2	KDELR2	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
APP	MGST3	psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
MFAP4	CRLF1	psi-mi:“MI:0914”(association)	0.350
KLK15	SPINT1	psi-mi:“MI:0914”(association)	0.350
GINM1	FAM234B	psi-mi:“MI:0914”(association)	0.350
KDELR2	CIAO1	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
UPK2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
OPALIN	FAM171A2	psi-mi:“MI:0914”(association)	0.350
ATP2A3	UBXN8	psi-mi:“MI:0914”(association)	0.350
NAAA	HAX1	psi-mi:“MI:0914”(association)	0.350
TNFSF14	HAX1	psi-mi:“MI:0914”(association)	0.350
VIPR1	SLC33A1	psi-mi:“MI:0914”(association)	0.350
SLC2A1	SLC33A1	psi-mi:“MI:0914”(association)	0.350

BioGRID (115): KDELR2 (Proximity Label-MS), KDELR2 (Proximity Label-MS), KDELR2 (Proximity Label-MS), KDELR2 (Proximity Label-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-RNA), KDELR2 (Affinity Capture-RNA), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Affinity Capture-MS), KDELR2 (Proximity Label-MS), BECN1 (FRET)

ESM2 similar proteins: A0A097ZPD8, A0A0E3D8M2, A0A0E3D8Q2, A0A140JWT2, A0A1B7YCX1, A0A2I6PJ07, A0A3G9H8P0, A9JPE3, E3UBL6, J7FIJ6, K2RU64, M1VJS5, O42580, O43731, O44017, O76767, O94270, P18413, P18414, P24390, P33946, P33947, P33948, P35402, P48583, P9WEX1, P9WEX7, P9WEY0, Q09473, Q2KJ37, Q4WLD2, Q569A6, Q5U305, Q5XHA2, Q5ZKX9, Q611C8, Q66JF2, Q68ES4, Q6NRS2, Q6P257

Diamond homologs: O42580, O43731, O44017, O76767, O94270, P18413, P18414, P24390, P33946, P33947, P33948, P35402, P48583, Q09473, Q2KJ37, Q569A6, Q5U305, Q5XHA2, Q5ZKX9, Q611C8, Q66JF2, Q68ES4, Q6P257, Q6PAB8, Q6PEH1, Q6PFS5, Q76NM1, Q7ZXS5, Q86JE5, Q8R1L4, Q8VWI1, Q99JH8, Q9CQM2, Q9ZTN2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	27
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1119976	NM_006854.4(KDELR2):c.13C>T (p.Arg5Trp)	Pathogenic
1119977	NM_006854.4(KDELR2):c.485A>G (p.Tyr162Cys)	Pathogenic
988961	NM_006854.4(KDELR2):c.448dup (p.His150fs)	Pathogenic
988964	NM_006854.4(KDELR2):c.360G>A (p.Trp120Ter)	Pathogenic

SpliceAI

1058 predictions. Top by Δscore:

Variant	Effect	Δscore
7:6463173:GTA:G	acceptor_gain	1.0000
7:6463173:GTAC:G	acceptor_loss	1.0000
7:6463174:TA:T	acceptor_gain	1.0000
7:6463175:AC:A	acceptor_loss	1.0000
7:6463176:C:CC	acceptor_gain	1.0000
7:6463182:T:TC	acceptor_gain	1.0000
7:6463185:C:CT	acceptor_gain	1.0000
7:6463186:A:T	acceptor_gain	1.0000
7:6466067:ATAC:A	donor_loss	1.0000
7:6466319:AGGAT:A	acceptor_gain	1.0000
7:6466320:GGAT:G	acceptor_gain	1.0000
7:6466323:TCTG:T	acceptor_loss	1.0000
7:6466324:C:CC	acceptor_gain	1.0000
7:6466324:CTG:C	acceptor_loss	1.0000
7:6466325:T:G	acceptor_loss	1.0000
7:6469621:A:C	donor_gain	1.0000
7:6469638:T:TA	donor_gain	1.0000
7:6469639:C:A	donor_gain	1.0000
7:6469660:TC:T	donor_gain	1.0000
7:6469661:C:CA	donor_gain	1.0000
7:6469661:CC:C	donor_gain	1.0000
7:6483961:GCTCA:G	donor_loss	1.0000
7:6483962:CTCAC:C	donor_loss	1.0000
7:6483963:TCAC:T	donor_loss	1.0000
7:6483964:CA:C	donor_loss	1.0000
7:6483965:ACCG:A	donor_loss	1.0000
7:6483966:C:CT	donor_loss	1.0000
7:6483985:T:TA	donor_gain	1.0000
7:6446100:TCCAC:T	acceptor_gain	0.9900
7:6446101:CCAC:C	acceptor_gain	0.9900

AlphaMissense

1364 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:6466125:C:G	G184R	1.000
7:6466271:A:G	L135P	1.000
7:6466277:G:T	P133Q	1.000
7:6484035:C:T	G8E	1.000
7:6484036:C:A	G8W	1.000
7:6466093:G:C	F194L	0.999
7:6466093:G:T	F194L	0.999
7:6466095:A:G	F194L	0.999
7:6466114:C:A	Q187H	0.999
7:6466114:C:G	Q187H	0.999
7:6466124:C:T	G184D	0.999
7:6466127:G:T	A183D	0.999
7:6466169:C:G	R169P	0.999
7:6466179:A:G	W166R	0.999
7:6466179:A:T	W166R	0.999
7:6466180:G:C	N165K	0.999
7:6466180:G:T	N165K	0.999
7:6466199:C:G	R159P	0.999
7:6466200:G:T	R159S	0.999
7:6466208:C:T	G156D	0.999
7:6466209:C:G	G156R	0.999
7:6466211:A:G	L155P	0.999
7:6466220:A:G	L152P	0.999
7:6466220:A:T	L152Q	0.999
7:6466277:G:C	P133R	0.999
7:6466278:G:A	P133S	0.999
7:6466278:G:T	P133T	0.999
7:6466283:A:T	I131N	0.999
7:6466286:G:T	A130D	0.999
7:6466287:C:G	A130P	0.999

dbSNP variants (sampled 300 via entrez): RS1000038533 (7:6461193 G>A), RS1000260888 (7:6476769 A>G), RS1000289132 (7:6466668 A>G), RS1000317508 (7:6471399 C>G,T), RS1000347057 (7:6471075 C>T), RS1000372849 (7:6466489 A>G), RS1000393164 (7:6480468 G>C), RS1000579811 (7:6480685 G>A,T), RS1000622884 (7:6485037 G>A,T), RS1000767507 (7:6481580 G>A,C), RS1000790395 (7:6481242 G>A), RS1000889653 (7:6467782 C>T), RS1000935061 (7:6475468 T>C), RS1001008049 (7:6462513 G>C), RS1001042165 (7:6462232 T>A,C)

Disease associations

OMIM: gene MIM:609024 | disease phenotypes: MIM:619131, MIM:259420

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta, type 21	Strong	Autosomal recessive
osteogenesis imperfecta	Supportive	Autosomal dominant

Mondo (3): osteogenesis imperfecta, type 21 (MONDO:0030861), osteogenesis imperfecta type 3 (MONDO:0009804), osteogenesis imperfecta (MONDO:0019019)

Orphanet (2): Osteogenesis imperfecta type 3 (Orphanet:216812), Osteogenesis imperfecta (Orphanet:666)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000767	Pectus excavatum
HP:0000926	Platyspondyly
HP:0000939	Osteoporosis
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001382	Joint hypermobility
HP:0001552	Barrel-shaped chest
HP:0001591	Bell-shaped thorax
HP:0001763	Pes planus
HP:0002645	Wormian bones
HP:0002650	Scoliosis
HP:0002673	Coxa valga
HP:0002757	Recurrent fractures
HP:0002812	Coxa vara
HP:0002979	Bowing of the legs
HP:0003593	Infantile onset
HP:0006488	Bowing of the arm
HP:0008081	Pes valgus
HP:0008873	Disproportionate short-limb short stature
HP:0011461	Fetal onset
HP:0011463	Childhood onset

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002629_2	Irritable bowel syndrome	5.000000e-06
GCST004131_9	Inflammatory bowel disease	4.000000e-08
GCST004133_37	Ulcerative colitis	2.000000e-06
GCST004599_47	Mean platelet volume	5.000000e-15
GCST004608_35	Granulocyte percentage of myeloid white cells	2.000000e-50
GCST004609_28	Monocyte percentage of white cells	5.000000e-45
GCST004625_94	Monocyte count	1.000000e-36
GCST004632_54	Lymphocyte percentage of white cells	2.000000e-13
GCST004633_66	Neutrophil percentage of white cells	7.000000e-25
GCST005951_155	Body mass index	1.000000e-08
GCST005977_1	Monocyte count	9.000000e-11
GCST010219_9	Attention deficit hyperactivity disorder (inattention symptoms)	3.000000e-07
GCST90002389_144	Lymphocyte percentage of white cells	5.000000e-30
GCST90002393_537	Monocyte count	2.000000e-75
GCST90002394_184	Monocyte percentage of white cells	8.000000e-89
GCST90002395_681	Mean platelet volume	6.000000e-34
GCST90002398_418	Neutrophil count	2.000000e-14
GCST90002399_165	Neutrophil percentage of white cells	5.000000e-53
GCST90002404_279	Red cell distribution width	7.000000e-17

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004340	body mass index
EFO:0004833	neutrophil count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C536044	Osteogenesis imperfecta, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066915 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.29	Kd	51.05	nM	CHEMBL5653589
7.29	ED50	51.05	nM	CHEMBL5653589
6.96	Kd	108.8	nM	CHEMBL3752910
6.96	ED50	108.8	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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	2148619: Binding affinity to human KDELR2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0510	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148619: Binding affinity to human KDELR2 incubated for 45 mins by Kinobead based pull down assay	kd	0.1088	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Cyclosporine	decreases expression, increases expression	3
sodium arsenite	increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
methylmercuric chloride	increases expression	1
bisphenol A	affects expression	1
methylselenic acid	decreases expression	1
salinomycin	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	increases expression	1
thifluzamide	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
eprenetapopt	affects expression, affects reaction	1
picoxystrobin	increases expression	1
Temozolomide	increases expression	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	increases expression	1
Diuron	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Piroxicam	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651661	Binding	Binding affinity to human KDELR2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2ZL	Abcam HEK293T KDELR2 KO	Transformed cell line	Female
CVCL_E2AA	HAP1 KDELR2 (-) 2	Cancer cell line	Male
CVCL_XP96	HAP1 KDELR2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT03118570	PHASE2	COMPLETED	A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	PHASE1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	PHASE1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)
NCT06086613	PHASE1	COMPLETED	A First-in-Human Study Evaluating AGA2115 in Adult Healthy Volunteers
NCT01061099	PHASE1	COMPLETED	Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta
NCT05125809	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Placebo for Osteogenesis Imperfecta
NCT03706482	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Boost Brittle Bones Before Birth
NCT04623606	PHASE1/PHASE2	UNKNOWN	Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones
NCT05559801	PHASE1/PHASE2	NOT_YET_RECRUITING	Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
NCT00001594	Not specified	COMPLETED	Evaluation and Intervention for the Effects of Osteogenesis Imperfecta
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease