Ehlers-Danlos syndrome, classic type

Summary

Ehlers-Danlos syndrome, classic type (MONDO:0007522) is a disease caused by variants in COL1A1 and COL5A1, with 13 cohort genes and 2 clinical trials. The dominant Reactome pathway is Fibronectin matrix formation (5 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal genes: COL1A1 (GenCC Definitive), COL5A1 (GenCC Definitive)
• Cohort genes: 13
• ClinVar variants: 300
• Phenotypes (HPO): 66
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

66 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001027	Soft, doughy skin	Very frequent (80-99%)
HP:0001030	Fragile skin	Very frequent (80-99%)
HP:0001065	Striae distensae	Very frequent (80-99%)
HP:0001073	Cigarette-paper scars	Very frequent (80-99%)
HP:0001075	Atrophic scars	Very frequent (80-99%)
HP:0002761	Generalized joint laxity	Very frequent (80-99%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001058	Poor wound healing	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003771	Pulp calcification	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0000015	Bladder diverticulum	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000139	Uterine prolapse	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000481	Abnormal cornea morphology	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0000993	Molluscoid pseudotumors	Occasional (5-29%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001386	Joint swelling	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001622	Premature birth	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001788	Premature rupture of membranes	Occasional (5-29%)
HP:0002035	Rectal prolapse	Occasional (5-29%)
HP:0002036	Hiatus hernia	Occasional (5-29%)
HP:0002616	Aortic root aneurysm	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0002999	Patellar dislocation	Occasional (5-29%)
HP:0003010	Prolonged bleeding time	Occasional (5-29%)
HP:0003083	Dislocated radial head	Occasional (5-29%)
HP:0003834	Shoulder dislocation	Occasional (5-29%)
HP:0004872	Incisional hernia	Occasional (5-29%)
HP:0004944	Dilatation of the cerebral artery	Occasional (5-29%)
HP:0004947	Arteriovenous fistula	Occasional (5-29%)
HP:0005294	Arterial dissection	Occasional (5-29%)
HP:0006243	Phalangeal dislocation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, classic type
Mondo ID	MONDO:0007522
Orphanet	287
SNOMED CT	715318006
UMLS	C4225429
MedGen	909864
GARD	0002088
Is cancer (heuristic)	no

Also known as: classic Ehlers-Danlos syndrome · classical Ehlers-Danlos syndrome · EDS I · EDS II · EDS, classic type · Ehlers-Danlos syndrome classic type · Ehlers-Danlos syndrome type 1 (formerly) · Ehlers-Danlos syndrome type 2 · Ehlers-Danlos syndrome type 2 (formerly) · Ehlers-Danlos syndrome, classic type · Ehlers-Danlos syndrome, type I · Ehlers-Danlos syndrome, type II

Data availability: 300 ClinVar variants · 7 GenCC gene-disease records · 44 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Ehlers-Danlos syndrome, classic type

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (2): Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos syndrome, classic type, 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

300 retrieved; paginated sample, class counts are floors:

81 conflicting classifications of pathogenicity, 62 benign/likely benign, 48 uncertain significance, 37 pathogenic, 28 benign, 20 likely benign, 15 likely pathogenic, 7 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
17343	NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425643	NM_000089.4(COL1A2):c.1009G>A (p.Gly337Ser)	COL1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
456800	NC_000007.14:g.(?94395012)(94399104_?)del	COL1A2	Pathogenic	criteria provided, single submitter
456840	NM_000089.4(COL1A2):c.433-2A>G	COL1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
526903	NC_000007.14:g.(?94395012)(94395818_?)del	COL1A2	Pathogenic	criteria provided, single submitter
584403	NC_000007.13:g.(?94037139)(94037712_?)dup	COL1A2	Pathogenic	criteria provided, single submitter
640462	NC_000007.13:g.(?94037139)(94038155_?)dup	COL1A2	Pathogenic	criteria provided, single submitter
802334	NM_000089.4(COL1A2):c.857_875del (p.Gly286fs)	COL1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
835669	NM_000089.4(COL1A2):c.2674-3T>G	COL1A2	Pathogenic	criteria provided, single submitter
860577	NM_000089.4(COL1A2):c.1289G>A (p.Gly430Glu)	COL1A2	Pathogenic	criteria provided, single submitter
934568	NM_000089.4(COL1A2):c.3286G>A (p.Gly1096Ser)	COL1A2	Pathogenic	criteria provided, single submitter
934873	NM_000089.4(COL1A2):c.2215G>A (p.Gly739Arg)	COL1A2	Pathogenic	criteria provided, single submitter
830862	NC_000002.12:g.(?188974480)(189580648_?)del	COL3A1	Pathogenic	criteria provided, single submitter
17185	NM_000093.5(COL5A1):c.4916G>C (p.Cys1639Ser)	COL5A1	Pathogenic	no assertion criteria provided
3068643	NM_000093.5(COL5A1):c.2785A>T (p.Lys929Ter)	COL5A1	Pathogenic	criteria provided, single submitter
374262	NM_000093.5(COL5A1):c.3762del (p.Gly1255fs)	COL5A1	Pathogenic	criteria provided, single submitter
375637	NM_000093.5(COL5A1):c.2203dup (p.Gln735fs)	COL5A1	Pathogenic	criteria provided, single submitter
417456	NC_000009.12:g.(?134701171)(134835204_?)del	COL5A1	Pathogenic	criteria provided, single submitter
451603	NM_000093.5(COL5A1):c.2140C>T (p.Gln714Ter)	COL5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
459648	NC_000009.12:g.(?134690892)(134763757_?)del	COL5A1	Pathogenic	criteria provided, single submitter
459680	NM_000093.5(COL5A1):c.3752dup (p.Pro1253fs)	COL5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
529307	NC_000009.12:g.(?134752569)(134752665_?)del	COL5A1	Pathogenic	criteria provided, single submitter
573641	NM_000093.5(COL5A1):c.1720-136_1929del	COL5A1	Pathogenic	criteria provided, single submitter
583819	NC_000009.12:g.(?134699889)(134700142_?)del	COL5A1	Pathogenic	criteria provided, single submitter
619958	NM_000093.5(COL5A1):c.4338+1G>A	COL5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
625555	GRCh37/hg19 9q34.3(chr9:137496881-137648441)	COL5A1	Pathogenic	criteria provided, single submitter
642115	NM_000093.5(COL5A1):c.5155G>T (p.Glu1719Ter)	COL5A1	Pathogenic	criteria provided, single submitter
655757	NC_000009.12:g.(?134642178)(134768473_?)del	COL5A1	Pathogenic	criteria provided, single submitter
662836	NC_000009.12:g.(?134690902)(134727407_?)del	COL5A1	Pathogenic	criteria provided, single submitter
802532	NC_000009.12:g.134824601del	COL5A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 50 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL1A1	Definitive	Autosomal dominant	Ehlers-Danlos syndrome, classic type	20
COL5A1	Definitive	Autosomal dominant	Ehlers-Danlos syndrome, classic type	7
COL5A2	Definitive	Autosomal dominant	Ehlers-Danlos syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL5A2	Orphanet:287	Classical Ehlers-Danlos syndrome
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
SLC2A10	Orphanet:3342	Arterial tortuosity syndrome
COL1A2	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A2	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A2	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A2	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A2	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A2	Orphanet:230851	Cardiac-valvular Ehlers-Danlos syndrome
COL1A2	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A2	Orphanet:314029	High bone mass osteogenesis imperfecta
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria
COL3A1	Orphanet:286	Vascular Ehlers-Danlos syndrome
COL3A1	Orphanet:636941	Vascular Ehlers-Danlos-polymicrogyria syndrome
COL3A1	Orphanet:86	Familial abdominal aortic aneurysm
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
MYH11	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	gencc,clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	gencc,clinvar
COL5A2	HGNC:2210	ENSG00000204262	P05997	Collagen alpha-2(V) chain	gencc,clinvar
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
SLC2A10	HGNC:13444	ENSG00000197496	O95528	Solute carrier family 2, facilitated glucose transporter member 10	clinvar
CASD1	HGNC:16014	ENSG00000127995	Q96PB1	N-acetylneuraminate (7)9-O-acetyltransferase	clinvar
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
THSD7B	HGNC:29348	ENSG00000144229	Q9C0I4	Thrombospondin type-1 domain-containing protein 7B	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	clinvar
ABO	HGNC:79	ENSG00000175164	P16442	Histo-blood group ABO system transferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL5A2	Collagen alpha-2(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
SLC2A10	Solute carrier family 2, facilitated glucose transporter member 10	Facilitative glucose transporter required for the development of the cardiovascular system.
CASD1	N-acetylneuraminate (7)9-O-acetyltransferase	Key enzyme in the biosynthesis of O-acetylated (O-Ac) sialoglycans such as gangliosides O-AcGD3 and O-AcGD2, which affect various processes such as cell-cell interactions, host-pathogen recognition.
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
MYH11	Myosin-11	Muscle contraction.
ABO	Histo-blood group ABO system transferase	This protein is the basis of the ABO blood group system.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.38

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	6.0×	0.570
Antibody/Immunoglobulin	1	2.2×	0.570
Kinase	1	2.1×	0.570
Enzyme (other)	2	1.8×	0.570
Scaffold/PPI	1	1.3×	0.647
Other/Unknown	7	1.0×	0.666

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL5A2	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
SLC2A10	Transporter	yes		Sugar/inositol_transpt, MFS_sugar_transport-like, Sugar_transporter_CS
CASD1	Enzyme (other)	yes	2.3.1.45	Cas1_AcylTrans_dom, Cyclin-like_sf, NXPE4_C
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
THSD7B	Other/Unknown	no		TSP1_rpt, TSP1_rpt_sf, TSP1_spondin_dom
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
ABO	Enzyme (other)	yes	2.4.1.37	Glyco_trans_6, Nucleotide-diphossugar_trans

Expression context

Cohort genes with no expression data: 0.

13 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	4
stromal cell of endometrium	4
skin of hip	3
tendon of biceps brachii	3
tibia	2
visceral pleura	2
right coronary artery	2
saphenous vein	1
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
bronchial epithelial cell	1
epithelium of bronchus	1
Ammon’s horn	1
adrenal tissue	1
postcentral gyrus	1
parietal pleura	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
COL5A2	266	ubiquitous	marker	tendon of biceps brachii, periodontal ligament, stromal cell of endometrium
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
SLC2A10	235	ubiquitous	marker	tibia, bronchial epithelial cell, epithelium of bronchus
CASD1	278	ubiquitous	marker	adrenal tissue, postcentral gyrus, Ammon’s horn
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
THSD7B	151	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, cortical plate
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer
ABO	169	broad	marker	tendon of biceps brachii, buccal mucosa cell, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
FLNA	5,321
TGFBR1	4,828
MYH11	3,818
COL3A1	3,629
MED12	3,322
COL5A1	2,600
COL5A2	2,286
SLC2A10	2,046
THSD7B	756

Intra-cohort edges

A	B	Sources
COL1A1	COL1A2	intact
COL1A1	COL3A1	string_interaction
COL1A1	COL5A1	intact, string_interaction
COL1A1	COL5A2	string_interaction
COL1A2	COL5A1	intact
COL3A1	COL5A1	string_interaction
COL3A1	COL5A2	string_interaction
COL3A1	SLC2A10	string_interaction
COL5A1	COL5A2	string_interaction
COL5A1	SLC2A10	string_interaction
COL5A2	SLC2A10	string_interaction
FLNA	MYH11	biogrid_interaction
MYH11	SLC2A10	string_interaction
SLC2A10	TGFBR1	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABO	P16442	151
TGFBR1	P36897	44
FLNA	P21333	26
COL1A1	P02452	14
COL3A1	P02461	11
COL1A2	P08123	5
MED12	Q93074	3
COL5A1	P20908	1
MYH11	P35749	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CASD1	Q96PB1	87.87
SLC2A10	O95528	74.78
THSD7B	Q9C0I4	67.23
COL5A2	P05997	53.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 101. Enrichment computed across 13 evidence-associated genes (11 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fibronectin matrix formation	5	259.6×	4e-10	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Syndecan interactions	5	192.3×	1e-09	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
MET activates PTK2 signaling	5	173.0×	1e-09	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Collagen chain trimerization	5	118.0×	8e-09	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Developmental Lineage of Pancreatic Ductal Cells	5	103.8×	1e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Assembly of collagen fibrils and other multimeric structures	5	91.1×	2e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Collagen degradation	5	79.9×	3e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Collagen biosynthesis and modifying enzymes	5	77.5×	3e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Non-integrin membrane-ECM interactions	5	70.2×	5e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
ECM proteoglycans	5	68.3×	5e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
Integrin cell surface interactions	5	61.1×	8e-08	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1
GP1b-IX-V activation signalling	3	259.6×	1e-06	COL1A1, COL1A2, FLNA
Scavenging by Class A Receptors	3	163.9×	5e-06	COL1A1, COL1A2, COL3A1
Defective VWF binding to collagen type I	2	692.1×	2e-05	COL1A1, COL1A2
Enhanced cleavage of VWF variant by ADAMTS13	2	519.1×	3e-05	COL1A1, COL1A2
Defective VWF cleavage by ADAMTS13 variant	2	519.1×	3e-05	COL1A1, COL1A2
Signaling by PDGF	3	69.2×	5e-05	COL5A1, COL5A2, COL3A1
NCAM1 interactions	3	67.7×	6e-05	COL5A1, COL5A2, COL3A1
Enhanced binding of GP1BA variant to VWF multimer:collagen	2	296.6×	9e-05	COL1A1, COL1A2
Defective binding of VWF variant to GPIb:IX:V	2	296.6×	9e-05	COL1A1, COL1A2
Anchoring fibril formation	2	138.4×	4e-04	COL1A1, COL1A2
Platelet Adhesion to exposed collagen	2	122.1×	5e-04	COL1A1, COL1A2
Crosslinking of collagen fibrils	2	103.8×	7e-04	COL1A1, COL1A2
RHO GTPases activate PAKs	2	98.9×	7e-04	FLNA, MYH11
Attachment of bacteria to epithelial cells	2	90.3×	9e-04	COL5A1, COL5A2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	3	23.8×	9e-04	COL1A1, COL1A2, COL3A1
Platelet Aggregation (Plug Formation)	2	79.9×	0.001	COL1A1, COL1A2
GPVI-mediated activation cascade	2	56.1×	0.002	COL1A1, COL1A2
Defective SLC2A10 causes arterial tortuosity syndrome (ATS)	1	1038.2×	0.003	SLC2A10
Loss of Function of TGFBR2 in Cancer	1	346.1×	0.009	TGFBR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	6	103.7×	2e-09	COL1A1, COL5A1, COL5A2, TGFBR1, COL1A2, COL3A1
skin development	4	136.4×	2e-06	COL5A1, COL5A2, SLC2A10, COL3A1
cellular response to amino acid stimulus	4	94.3×	5e-06	COL1A1, COL5A2, COL1A2, COL3A1
negative regulation of endodermal cell differentiation	2	1296.3×	3e-05	COL5A1, COL5A2
skeletal system development	4	38.7×	1e-04	COL1A1, COL5A2, TGFBR1, COL1A2
eye morphogenesis	2	648.1×	1e-04	COL5A1, COL5A2
blood vessel development	3	86.4×	2e-04	COL1A1, COL5A1, COL1A2
elastic fiber assembly	2	235.7×	8e-04	COL3A1, MYH11
skin morphogenesis	2	216.1×	9e-04	COL1A1, COL1A2
collagen biosynthetic process	2	162.0×	0.001	COL1A1, COL5A1
supramolecular fiber organization	2	162.0×	0.001	COL5A1, COL3A1
transforming growth factor beta receptor signaling pathway	3	36.7×	0.001	TGFBR1, COL1A2, COL3A1
negative regulation of connective tissue growth factor production	1	1296.3×	0.008	SLC2A10
extracellular structure organization	1	1296.3×	0.008	TGFBR1
integrin biosynthetic process	1	1296.3×	0.008	COL5A1
protein heterotrimerization	1	1296.3×	0.008	COL1A2
cellular response to vitamin E	1	1296.3×	0.008	COL1A1
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	1296.3×	0.008	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	1296.3×	0.008	FLNA
positive regulation of epithelial to mesenchymal transition	2	48.9×	0.008	COL1A1, TGFBR1
heart development	3	18.2×	0.008	TGFBR1, MED12, COL3A1
cellular response to transforming growth factor beta stimulus	2	42.5×	0.010	COL1A1, TGFBR1
cellular response to fluoride	1	648.1×	0.013	COL1A1
negative regulation of proteoglycan biosynthetic process	1	648.1×	0.013	SLC2A10
epicardium morphogenesis	1	648.1×	0.013	TGFBR1
wound healing	2	35.0×	0.013	TGFBR1, COL3A1
skeletal muscle myosin thick filament assembly	1	432.1×	0.014	MYH11
transforming growth factor beta1 production	1	432.1×	0.014	COL3A1
tooth mineralization	1	432.1×	0.014	COL1A1
limb joint morphogenesis	1	432.1×	0.014	COL3A1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 10

Druggability breadth: 8 of 13 evidence-associated genes (62%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TGFBR1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
MED12	1	2
FLNA	1	2
COL1A1	0	0
COL5A1	0	0
COL5A2	0	0
SLC2A10	0	0
CASD1	0	0
COL1A2	0	0
COL3A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1
CRIZOTINIB	4	TGFBR1
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1
GALUNISERTIB	2	TGFBR1
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1
DANUSERTIB	2	TGFBR1
R-406	2	TGFBR1
AT-9283	2	TGFBR1
ZILURGISERTIB	2	TGFBR1
TOZASERTIB	2	TGFBR1
KER-047	2	TGFBR1
MOLIBRESIB	2	FLNA, MED12
GSK-1070916	1	TGFBR1
TAK-901	1	TGFBR1
XL-228	1	TGFBR1
MK-5108	1	TGFBR1
LY-3200882	1	TGFBR1
CYC-116	1	TGFBR1
PF-06952229	1	TGFBR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
COL1A1	8	Binding:8
FLNA	7	Binding:7
MED12	6	Binding:6
ABO	6	Binding:6
COL1A2	4	Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
CASD1	2.3.1.45	N-acetylneuraminate 9-O-acetyltransferase
ABO	2.4.1.37, 2.4.1.40, 2.4.1.88	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, globoside alpha-N-acetylgalactosaminyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TGFBR1	541

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1
CRIZOTINIB	4	TGFBR1
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1
GALUNISERTIB	2	TGFBR1
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1
DANUSERTIB	2	TGFBR1
R-406	2	TGFBR1
AT-9283	2	TGFBR1
ZILURGISERTIB	2	TGFBR1
TOZASERTIB	2	TGFBR1
KER-047	2	TGFBR1
MOLIBRESIB	2	FLNA, MED12
GSK-1070916	1	TGFBR1
TAK-901	1	TGFBR1
XL-228	1	TGFBR1
MK-5108	1	TGFBR1
LY-3200882	1	TGFBR1
CYC-116	1	TGFBR1
PF-06952229	1	TGFBR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TGFBR1
B	Phased (≥1) drug, not yet approved	2	MED12, FLNA
C	Druggable family + PDB, no drug	1	ABO
D	Druggable family + AlphaFold only, no drug	2	SLC2A10, CASD1
E	Difficult family or no structure, no drug	7	COL1A1, COL5A1, COL5A2, COL1A2, COL3A1, THSD7B, MYH11

Undrugged target profiles

10 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL1A1	8	—
COL5A1	0	—
COL5A2	0	—
SLC2A10	0	—
CASD1	0	—
COL1A2	4	—
COL3A1	0	—
THSD7B	0	—
MYH11	0	—
ABO	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS