COL5A2

Summary

COL5A2 (collagen type V alpha 2 chain, HGNC:2210) is a protein-coding gene on chromosome 2q32.2, encoding Collagen alpha-2(V) chain (P05997). Type V collagen is a member of group I collagen (fibrillar forming collagen).

This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II.

Source: NCBI Gene 1290 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, classic type (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 2,393 total — 26 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 74
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000393

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2210
Approved symbol	COL5A2
Name	collagen type V alpha 2 chain
Location	2q32.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204262
Ensembl biotype	protein_coding
OMIM	120190
Entrez	1290

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000374866, ENST00000470524, ENST00000618828, ENST00000649966, ENST00000858728, ENST00000858729

RefSeq mRNA: 1 — MANE Select: NM_000393 NM_000393

CCDS: CCDS33350

Canonical transcript exons

ENST00000374866 — 54 exons

Exon	Start	End
ENSE00001340085	189039272	189039563
ENSE00001464877	189066390	189066497
ENSE00001464879	189066729	189066782
ENSE00001464880	189068015	189068113
ENSE00001464881	189068226	189068270
ENSE00001464882	189068786	189068884
ENSE00001464883	189072040	189072093
ENSE00001464885	189075393	189075437
ENSE00001464906	189034916	189035155
ENSE00001464909	189036616	189036803
ENSE00001464912	189041586	189041693
ENSE00001464914	189042720	189042773
ENSE00001464915	189043151	189043258
ENSE00001464916	189045179	189045232
ENSE00001464918	189045800	189045907
ENSE00001464919	189048209	189048262
ENSE00001464921	189049347	189049454
ENSE00001464924	189050569	189050676
ENSE00001464926	189051320	189051481
ENSE00001464928	189052172	189052225
ENSE00001464931	189052749	189052802
ENSE00001464933	189052911	189053018
ENSE00001464936	189053424	189053477
ENSE00001464939	189053895	189053948
ENSE00001464940	189054159	189054212
ENSE00001464942	189056973	189057026
ENSE00001464956	189063010	189063063
ENSE00001464958	189063172	189063270
ENSE00001464960	189063980	189064033
ENSE00001464962	189064557	189064655
ENSE00001464964	189065004	189065057
ENSE00001950594	189031898	189034216
ENSE00002207962	189085160	189085213
ENSE00002246300	189098727	189098759
ENSE00002259894	189083984	189084037
ENSE00002261192	189092310	189092420
ENSE00002265614	189086726	189086770
ENSE00002274959	189097277	189097330
ENSE00002277030	189110225	189110449
ENSE00002282195	189080990	189081043
ENSE00002296303	189079063	189079107
ENSE00002298782	189088695	189088772
ENSE00002298836	189079978	189080031
ENSE00002302801	189078516	189078569
ENSE00002308931	189100107	189100139
ENSE00002320301	189085719	189085772
ENSE00002480324	189104264	189104277
ENSE00003460898	189058429	189058527
ENSE00003512494	189062865	189062918
ENSE00003535763	189057320	189057427
ENSE00003626834	189061562	189061615
ENSE00003630751	189060730	189060783
ENSE00003672012	189058849	189058893
ENSE00003840767	189179508	189179761

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 99.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 154.4586 / max 4681.6221, expressed in 1309 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32857	145.8622	1223
32858	7.2940	987
32859	1.2071	115
32842	0.0953	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.59	gold quality
periodontal ligament	UBERON:0008266	99.54	gold quality
stromal cell of endometrium	CL:0002255	99.33	gold quality
skin of hip	UBERON:0001554	99.17	gold quality
tibia	UBERON:0000979	98.97	gold quality
cartilage tissue	UBERON:0002418	98.91	gold quality
visceral pleura	UBERON:0002401	98.26	gold quality
pleura	UBERON:0000977	97.94	gold quality
parietal pleura	UBERON:0002400	97.87	gold quality
synovial joint	UBERON:0002217	97.50	gold quality
smooth muscle tissue	UBERON:0001135	97.01	gold quality
layer of synovial tissue	UBERON:0007616	97.00	gold quality
colonic epithelium	UBERON:0000397	96.94	gold quality
gall bladder	UBERON:0002110	96.90	gold quality
saphenous vein	UBERON:0007318	96.82	gold quality
CA1 field of hippocampus	UBERON:0003881	96.42	gold quality
blood vessel layer	UBERON:0004797	96.41	gold quality
placenta	UBERON:0001987	96.32	gold quality
decidua	UBERON:0002450	96.24	gold quality
descending thoracic aorta	UBERON:0002345	95.87	gold quality
upper leg skin	UBERON:0004262	95.83	gold quality
endometrium	UBERON:0001295	95.69	gold quality
tendon	UBERON:0000043	95.33	gold quality
pylorus	UBERON:0001166	95.31	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.65	gold quality
mammary duct	UBERON:0001765	94.60	gold quality
thoracic aorta	UBERON:0001515	94.52	gold quality
cardia of stomach	UBERON:0001162	94.49	gold quality
ascending aorta	UBERON:0001496	94.35	gold quality
upper arm skin	UBERON:0004263	94.34	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	1188.12
E-MTAB-7407	yes	1041.32
E-ENAD-20	yes	691.78
E-HCAD-25	yes	629.00
E-GEOD-83139	yes	587.30
E-MTAB-7249	yes	476.99
E-HCAD-13	yes	268.16
E-MTAB-10287	yes	114.61
E-MTAB-6701	yes	59.48
E-HCAD-10	yes	49.24
E-MTAB-8410	yes	44.61
E-ANND-3	yes	27.42
E-CURD-112	yes	19.43
E-CURD-46	yes	15.43
E-MTAB-6678	yes	12.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, MYBL2, MYRF, PGR, SMAD3, SMAD7, SP1, TCF3

miRNA regulators (miRDB)

177 targeting COL5A2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• Mutations in the COL5A2 gene have been identified by DNA sequence analysis in 10 patients with spontaneous vertebral artery dissections. (PMID:11940702)
• analysis of processing of the Pro-alpha1(V)Pro-alpha2(V)Pro-alpha3(V) procollagen heterotrimer (PMID:15136578)
• In the eye, COL5A1 and COL5A2 mutations manifest as abnormally thin and steep corneas with floppy eyelids. (PMID:16431952)
• The formation of alpha1(V) homotrimers was considerably favored over the heterotrimer alpha1(V)alpha2(V). (PMID:20625483)
• Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. (PMID:20648054)
• role of mutations in Ehlers-Danlos syndrome (Review) (PMID:20847697)
• Before but not after developing bronchiolitis obliterans, lung transplantation patients had antibodies to Col-V, alpha2(V). Pep5-8 to alpha1,2(V) and pep9-14 to alpha2(V)were immunodominant. (PMID:22132895)
• This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous preterm delivery. (PMID:22208904)
• study shows that over 90% of patients, which strictly satisfy all major Villefranche criteria for classic Ehlers-Danlos Syndrome (EDS)harbor a type V collagen defect which indicates that this is the major–if not only–cause of classic EDS (PMID:22696272)
• Col5a2 shows predictive potential in myocardial infarction , and in principle may represent a novel candidate marker for the identification and treatment of ischemic cardiovascular disease (PMID:23574622)
• data confirm that COL5A1 and COL5A2 are the major, if not the only, genes involved in classic Ehlers-danlos syndrome (PMID:23587214)
• COL5A2(+/-) humans, although unlikely to present with frank classic Ehlers-Danlos syndrome, are likely to have fragile connective tissues with increased susceptibility to trauma and certain chronic pathologic conditions. (PMID:25987251)
• Mutations affecting COL5A1 or COL5A2 are responsible for spectrum of mucocutaneous, ocular and facial features in 62 classical Ehlers-Danlos syndrome patients. (PMID:28485813)
• Bladder cancer patients in COL5A2 low expression group were associated with better invasiveness (P < .0001), tumor grade (P=.001), T staging (P < .0001), N staging (P = .002), and a trend of better M staging (P = .053) than those in COL5A2 high expression group. These results indicated that COL5A2 might promote the progression of Bladder Cancer cells. (PMID:29517678)
• COL5A1 is an unfavorable factor for tumorigenesis, clinicopathological outcomes, and prognosis, whereas COL5A2 is only a favorable factor for prognosis in tongue squamous cell carcinoma (PMID:30972812)
• Foxf2 and Smad6 co-regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion. (PMID:32022446)
• Arterial complications in classical Ehlers-Danlos syndrome: a case series. (PMID:32467296)
• COL5A2 as a potential clinical biomarker for gastric cancer and renal metastasis. (PMID:33607786)
• High expression of COL5A2, a member of COL5 family, indicates the poor survival and facilitates cell migration in gastric cancer. (PMID:33739392)
• Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1. (PMID:33974636)
• Phenotype of COL3A1/COL5A2 deletion patients. (PMID:35964930)
• Collagen type V alpha 2 promotes the development of gastric cancer via M2 macrophage polarization. (PMID:37082997)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	col5a2a	ENSDARG00000031678
mus_musculus	Col5a2	ENSMUSG00000026042
rattus_norvegicus	Col5a2	ENSRNOG00000003736

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL2A1 (ENSG00000139219), COL6A1 (ENSG00000142156), COL6A2 (ENSG00000142173), EDA (ENSG00000158813), COL26A1 (ENSG00000160963), COL1A2 (ENSG00000164692), COL3A1 (ENSG00000168542), COL4A3 (ENSG00000169031), COL22A1 (ENSG00000169436), COL24A1 (ENSG00000171502), COL18A1 (ENSG00000182871), EMID1 (ENSG00000186998), COL4A1 (ENSG00000187498), COL4A5 (ENSG00000188153), COL25A1 (ENSG00000188517), COL27A1 (ENSG00000196739), COL13A1 (ENSG00000197467), COL4A6 (ENSG00000197565), COL11A2 (ENSG00000204248), COL15A1 (ENSG00000204291), COLQ (ENSG00000206561), COL28A1 (ENSG00000215018)

Protein

Protein identifiers

Collagen alpha-2(V) chain — P05997 (reviewed: P05997)

All UniProt accessions (3): A0A087WYX9, A0A3B3IRH9, P05997

UniProt curated annotations — full annotation on UniProt →

Function. Type V collagen is a member of group I collagen (fibrillar forming collagen). It is a minor connective tissue component of nearly ubiquitous distribution. Type V collagen binds to DNA, heparan sulfate, thrombospondin, heparin, and insulin. Type V collagen is a key determinant in the assembly of tissue-specific matrices.

Subunit / interactions. Trimers of two alpha 1(V) and one alpha 2(V) chains in most tissues and trimers of one alpha 1(V), one alpha 2(V), and one alpha 3(V) chains in placenta.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Post-translational modifications. Prolines at the third position of the tripeptide repeating unit (G-X-P) are hydroxylated in some or all of the chains. Probably 3-hydroxylated on Pro-919 and Pro-1156 by LEPREL1.

Disease relevance. Ehlers-Danlos syndrome, classic type, 2 (EDSCL2) [MIM:130010] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are joint hypermobility and dislocation, and fragile, bruisable skin. EDSCL2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal propeptide, also known as COLFI domain, have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. It binds a calcium ion which is essential for its function.

Similarity. Belongs to the fibrillar collagen family.

RefSeq proteins (1): NP_000384* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000885	Fib_collagen_C	Domain
IPR001007	VWF_dom	Domain
IPR008160	Collagen	Repeat
IPR050149	Collagen_superfamily	Family

Pfam: PF00093, PF01391, PF01410

UniProt features (83 total): sequence conflict 27, compositionally biased region 19, sequence variant 8, short sequence motif 7, modified residue 7, binding site 4, disulfide bond 3, domain 2, glycosylation site 2, signal peptide 1, chain 1, propeptide 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05997-F1	53.15	0.16

Functional residue map

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

Ligand- & substrate-binding residues (4): 1314; 1316; 1317; 1322

Post-translational modifications (7): 290, 293, 296, 611, 617, 919, 1156

Disulfide bonds (3): 1296–1328, 1336–1497, 1405–1450

Glycosylation sites (2): 1262, 1400

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1566977	Fibronectin matrix formation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-186797	Signaling by PDGF
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000170	Syndecan interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-419037	NCAM1 interactions
R-HSA-8874081	MET activates PTK2 signaling
R-HSA-8948216	Collagen chain trimerization
R-HSA-9638630	Attachment of bacteria to epithelial cells
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells

MSigDB gene sets: 510 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, MODULE_52, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOCC_COLLAGEN_TRIMER, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH

GO Biological Process (8): skeletal system development (GO:0001501), collagen fibril organization (GO:0030199), skin development (GO:0043588), eye morphogenesis (GO:0048592), cellular response to amino acid stimulus (GO:0071230), negative regulation of endodermal cell differentiation (GO:1903225), animal organ development (GO:0048513), system development (GO:0048731)

GO Molecular Function (5): extracellular matrix structural constituent conferring tensile strength (GO:0030020), SMAD binding (GO:0046332), metal ion binding (GO:0046872), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), collagen type V trimer (GO:0005588), collagen type XI trimer (GO:0005592), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), collagen trimer (GO:0005581), fibrillar collagen trimer (GO:0005583)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Extracellular matrix organization	4
Collagen formation	2
Degradation of the extracellular matrix	1
Signaling by Receptor Tyrosine Kinases	1
Non-integrin membrane-ECM interactions	1
NCAM signaling for neurite out-growth	1
MET promotes cell motility	1
Collagen biosynthesis and modifying enzymes	1
Biofilm formation	1
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
fibrillar collagen trimer	2
system development	1
extracellular matrix organization	1
animal organ development	1
eye development	1
sensory organ morphogenesis	1
response to amino acid	1
cellular response to acid chemical	1
endodermal cell differentiation	1
negative regulation of cell differentiation	1
regulation of endodermal cell differentiation	1
multicellular organism development	1
extracellular matrix structural constituent	1
protein binding	1
cation binding	1
structural molecule activity	1
extracellular matrix	1
binding	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
protein-containing complex	1
collagen trimer	1
fibrillar collagen complex	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

2252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL5A2	COL3A1	P02461	962
COL5A2	COL1A2	P02464	949
COL5A2	COL5A1	P20908	928
COL5A2	COL1A1	P02452	912
COL5A2	COL11A1	P12107	855
COL5A2	COL6A3	P12111	792
COL5A2	FN1	P02751	756
COL5A2	COL4A2	P08572	749
COL5A2	TNXB	P22105	746
COL5A2	COL4A1	P02462	731
COL5A2	PLOD1	Q02809	714
COL5A2	THBS2	P35442	697
COL5A2	BGN	P13247	694
COL5A2	LUM	P51884	668
COL5A2	COL6A1	P12109	662

IntAct

15 interactions, top by confidence:

A	B	Type	Score
MMP2	COL4A1	psi-mi:“MI:0914”(association)	0.640
LAIR2	LAMA5	psi-mi:“MI:0914”(association)	0.530
COL5A2	NES	psi-mi:“MI:0915”(physical association)	0.400
TGM2	SRGAP3	psi-mi:“MI:0914”(association)	0.350
Fbxw11	CTNNB1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
	CCN1	psi-mi:“MI:0914”(association)	0.350
LAIR2	PLOD3	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
KLHL15	DNAJB5	psi-mi:“MI:0914”(association)	0.350
P4HA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350
CTNNA1	ILVBL	psi-mi:“MI:0914”(association)	0.350
GATA2	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): COL5A2 (Proximity Label-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), NES (Proximity Label-MS), COL5A2 (Proximity Label-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), COL5A2 (Affinity Capture-MS), HIST1H1E (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: C0HJN4, C0HJN5, C0HJN6, C0HJN8, C0HJP0, C0HJP1, C0HJP2, C0HJP4, C0HJP5, C0HJP6, C0HJP8, C0HLG8, C0HLH0, C0HLH2, C0HLH4, C0HLH6, C0HLI0, C0HLI2, C0HLI4, C0HLI6, C0HLI8, C0HLJ0, C0HLJ2, C0HLJ4, C0HLJ6, C0HLJ8, C0HLK0, C0HM85, C0HM86, C0HM87, C0HM88, C0HM89, C0HM90, C0HM91, C0HM92, C0HM94, C0HM95, O42350, O46392, O93484

Diamond homologs: A0MSJ1, C7DZK3, O42350, O88207, P02452, P02457, P02458, P02459, P02460, P02461, P02466, P05997, P08121, P12105, P12107, P13941, P13942, P20908, P20909, Q17RW2, Q30D77, Q32S24, Q3U962, Q5QNQ9, Q60467, Q61245, Q64739, Q6P4Z2, Q80ZF0, Q8IZC6, Q91717, Q9JI03, Q9YIB4, B0UZC8, B2RUY7, P28481, Q2TAL6, Q505H4, Q7T3Q2, Q8AWW5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BMP1	“up-regulates activity”	COL5A2	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

2393 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	38
Uncertain significance	862
Likely benign	966
Benign	145

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1451305	NM_000393.5(COL5A2):c.971G>A (p.Gly324Asp)	Pathogenic
1453409	NM_000393.5(COL5A2):c.387del (p.Arg130fs)	Pathogenic
1455118	NM_000393.5(COL5A2):c.386del (p.Gly129fs)	Pathogenic
1703524	GRCh37/hg19 2q32.1-34(chr2:185697659-213002074)	Pathogenic
17196	NM_000393.5(COL5A2):c.1924-2_1928del	Pathogenic
17197	NM_000393.5(COL5A2):c.2031+1G>T	Pathogenic
1895397	NM_000393.5(COL5A2):c.1105G>A (p.Gly369Ser)	Pathogenic
2001551	NM_000393.5(COL5A2):c.1402-2A>G	Pathogenic
2003068	NM_000393.5(COL5A2):c.1066C>T (p.Arg356Ter)	Pathogenic
2029847	NM_000393.5(COL5A2):c.3201+1G>T	Pathogenic
213101	NM_000393.5(COL5A2):c.1977G>A (p.Pro659=)	Pathogenic
2740545	NM_000393.5(COL5A2):c.2137C>T (p.Arg713Ter)	Pathogenic
2769823	NM_000393.5(COL5A2):c.2769+2dup	Pathogenic
2818690	NM_000393.5(COL5A2):c.3406C>T (p.Arg1136Ter)	Pathogenic
4681568	NM_000393.5(COL5A2):c.3654_3671del (p.1219PPG[1])	Pathogenic
4715994	NM_000393.5(COL5A2):c.550_553dup (p.Asp185fs)	Pathogenic
4726403	NM_000393.5(COL5A2):c.4220del (p.Asn1407fs)	Pathogenic
518425	NM_000393.5(COL5A2):c.2553+2del	Pathogenic
518426	NM_000393.5(COL5A2):c.4298del (p.Ile1433fs)	Pathogenic
518427	NM_000393.5(COL5A2):c.3148-2A>G	Pathogenic
518428	NM_000393.5(COL5A2):c.1617+4A>G	Pathogenic
576400	NM_000393.5(COL5A2):c.1924-4C>G	Pathogenic
641300	NM_000393.5(COL5A2):c.690+5G>T	Pathogenic
862627	NM_000393.5(COL5A2):c.3147+1G>A	Pathogenic
863014	NM_000393.5(COL5A2):c.2919dup (p.Asp974fs)	Pathogenic
976315	NM_000393.5(COL5A2):c.1159-60_2031+62dup	Pathogenic
1028727	NM_000393.5(COL5A2):c.2833G>A (p.Gly945Arg)	Likely pathogenic
1324127	NM_000393.5(COL5A2):c.98-1G>T	Likely pathogenic
1497020	NC_000002.11:g.(?189913190)(189918176_?)del	Likely pathogenic
1508026	NM_000393.5(COL5A2):c.2130+1G>A	Likely pathogenic

SpliceAI

5804 predictions. Top by Δscore:

Variant	Effect	Δscore
2:189034212:CGCTT:C	acceptor_gain	1.0000
2:189034214:CTT:C	acceptor_gain	1.0000
2:189034215:TT:T	acceptor_gain	1.0000
2:189034216:TCT:T	acceptor_loss	1.0000
2:189034217:C:CC	acceptor_gain	1.0000
2:189034217:CTG:C	acceptor_loss	1.0000
2:189034223:T:C	acceptor_gain	1.0000
2:189034223:T:TC	acceptor_gain	1.0000
2:189034911:CT:C	donor_loss	1.0000
2:189034912:TTACA:T	donor_loss	1.0000
2:189034913:TAC:T	donor_loss	1.0000
2:189034914:A:AC	donor_gain	1.0000
2:189034914:ACAG:A	donor_loss	1.0000
2:189034915:C:CA	donor_gain	1.0000
2:189034915:CA:C	donor_gain	1.0000
2:189034915:CAG:C	donor_gain	1.0000
2:189034915:CAGA:C	donor_gain	1.0000
2:189034915:CAGAG:C	donor_gain	1.0000
2:189035151:GCGAA:G	acceptor_gain	1.0000
2:189035152:CGAA:C	acceptor_gain	1.0000
2:189035152:CGAAC:C	acceptor_gain	1.0000
2:189035153:GAA:G	acceptor_gain	1.0000
2:189035154:AA:A	acceptor_gain	1.0000
2:189035156:C:CC	acceptor_gain	1.0000
2:189035156:C:CG	acceptor_loss	1.0000
2:189035157:T:C	acceptor_loss	1.0000
2:189036611:ATTAC:A	donor_loss	1.0000
2:189036613:TA:T	donor_loss	1.0000
2:189036614:A:AT	donor_loss	1.0000
2:189036617:TGAG:T	donor_gain	1.0000

AlphaMissense

9422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:189036746:C:G	C1328S	1.000
2:189036747:A:T	C1328S	1.000
2:189039309:A:C	C1296W	1.000
2:189039310:C:T	C1296Y	1.000
2:189039311:A:G	C1296R	1.000
2:189043185:C:T	G1146D	1.000
2:189043186:C:G	G1146R	1.000
2:189050630:C:T	G993E	1.000
2:189050631:C:G	G993R	1.000
2:189050631:C:T	G993R	1.000
2:189064023:C:T	G576E	1.000
2:189110356:C:G	C64S	1.000
2:189110357:A:T	C64S	1.000
2:189110385:C:A	W54C	1.000
2:189110385:C:G	W54C	1.000
2:189034920:C:G	C1450S	0.999
2:189034921:A:T	C1450S	0.999
2:189035054:A:C	C1405W	0.999
2:189035055:C:G	C1405S	0.999
2:189035055:C:T	C1405Y	0.999
2:189035056:A:G	C1405R	0.999
2:189035056:A:T	C1405S	0.999
2:189035073:T:G	Q1399P	0.999
2:189035094:A:G	L1392P	0.999
2:189036722:C:G	C1336S	0.999
2:189036723:A:T	C1336S	0.999
2:189036745:G:C	C1328W	0.999
2:189036746:C:T	C1328Y	0.999
2:189036747:A:G	C1328R	0.999
2:189039301:A:G	L1299P	0.999

dbSNP variants (sampled 300 via entrez): RS1000016557 (2:189075274 A>C,T), RS1000036524 (2:189398978 T>C), RS1000037028 (2:189346792 G>C), RS1000049642 (2:189259116 A>G), RS1000055478 (2:189341186 A>C), RS1000074061 (2:189436485 T>C), RS1000084966 (2:189076917 CAA>C,CA,CAAA), RS1000086589 (2:189182521 C>A,T), RS1000088145 (2:189316473 T>C), RS1000090351 (2:189069883 G>C), RS1000093796 (2:189123955 C>A,T), RS1000100795 (2:189441546 C>A), RS1000109466 (2:189257772 A>G), RS1000112160 (2:189301903 G>A), RS1000129391 (2:189109276 T>A,C)

Disease associations

OMIM: gene MIM:120190 | disease phenotypes: MIM:130000, MIM:607086, MIM:130010, MIM:612313, MIM:609192, MIM:154700, MIM:148300, MIM:187350, MIM:308350, MIM:617168, MIM:259420

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome	Definitive	Autosomal dominant
Ehlers-Danlos syndrome, classic type, 2	Strong	Autosomal dominant
Ehlers-Danlos syndrome, classic type	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, classic type	Definitive	AD

Mondo (16): Ehlers-Danlos syndrome, classic type, 1 (MONDO:0019567), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Ehlers-Danlos syndrome, classic type, 2 (MONDO:0019568), Ehlers-Danlos syndrome (MONDO:0020066), connective tissue disorder (MONDO:0003900), Ehlers-Danlos syndrome, classic type (MONDO:0007522), chromosome 2q32-q33 deletion syndrome (MONDO:0012864), Loeys-Dietz syndrome (MONDO:0018954), Marfan syndrome (MONDO:0007947), Ehlers-Danlos syndrome, arthrochalasia type (MONDO:0007525), thrombocytopenia (MONDO:0002049), keratoconus (MONDO:0015486), telecanthus (MONDO:0008537), genetic developmental and epileptic encephalopathy (MONDO:0100062), aortic aneurysm, familial thoracic 10 (MONDO:0014950)

Orphanet (18): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Classical Ehlers-Danlos syndrome (Orphanet:287), OBSOLETE: Ehlers-Danlos syndrome type 2 (Orphanet:90318), Ehlers-Danlos syndrome (Orphanet:98249), 2q32q33 deletion syndrome (Orphanet:251019), Loeys-Dietz syndrome (Orphanet:60030), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Arthrochalasia Ehlers-Danlos syndrome (Orphanet:1899), OBSOLETE: Ehlers-Danlos syndrome type 7A (Orphanet:99875), OBSOLETE: Ehlers-Danlos syndrome type 7B (Orphanet:99876), Syndromic telecanthus (Orphanet:98575), Osteogenesis imperfecta type 3 (Orphanet:216812), Osteogenesis imperfecta (Orphanet:666), OBSOLETE: Ehlers-Danlos syndrome type 1 (Orphanet:90309)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000139	Uterine prolapse
HP:0000286	Epicanthus
HP:0000481	Abnormal cornea morphology
HP:0000938	Osteopenia
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0000993	Molluscoid pseudotumors
HP:0001027	Soft, doughy skin
HP:0001030	Fragile skin
HP:0001058	Poor wound healing
HP:0001063	Acrocyanosis
HP:0001065	Striae distensae
HP:0001073	Cigarette-paper scars
HP:0001075	Atrophic scars
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001278	Orthostatic hypotension
HP:0001324	Muscle weakness
HP:0001374	Congenital hip dislocation
HP:0001382	Joint hypermobility
HP:0001386	Joint swelling
HP:0001537	Umbilical hernia
HP:0001622	Premature birth
HP:0001634	Mitral valve prolapse
HP:0001653	Mitral regurgitation
HP:0001704	Tricuspid valve prolapse

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003059_5	Parkinson’s disease	1.000000e-06
GCST009391_1328	Metabolite levels	7.000000e-06
GCST010698_39	Subcortical volume (min-P)	9.000000e-26
GCST010699_36	Brain morphology (min-P)	9.000000e-09
GCST010700_26	Cortical thickness (MOSTest)	9.000000e-52
GCST010701_48	Cortical surface area (MOSTest)	2.000000e-18
GCST010702_50	Subcortical volume (MOSTest)	8.000000e-10
GCST010703_340	Brain morphology (MOSTest)	3.000000e-10
GCST90000025_833	Appendicular lean mass	7.000000e-15
GCST90014033_19	Haemorrhoidal disease	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010361	lysophosphatidylcholine 18:2 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004980	appendicular lean mass

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D007640	Keratoconus	C11.204.627
D055947	Loeys-Dietz Syndrome	C05.660.207.532; C14.907.055.239.587; C14.907.109.139.587; C16.131.077.537; C16.320.510
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C567350	Chromosome 2q32-Q33 Deletion Syndrome (supp.)
C562625	Ehlers-Danlos Syndrome, Type VII, Autosomal Dominant (supp.)
C536194	Ehlers-Danlos syndrome type 1 (supp.)
C536195	Ehlers-Danlos syndrome type 2 (supp.)
C536044	Osteogenesis imperfecta, type 3 (supp.)
C562941	Telecanthus (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364188 (PROTEIN COMPLEX GROUP)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	7
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases expression, increases methylation	7
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	5
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects splicing, decreases expression, increases expression	3
Estradiol	increases expression, affects expression, affects cotreatment, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
cobaltous chloride	decreases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
N-Nitrosopyrrolidine	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, decreases reaction	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
bisphenol F	decreases methylation, affects cotreatment	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	decreases reaction, affects binding	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions