Connective tissue disease: genes and variants

Genes linked to Connective tissue disease

• COL2A1: Collagen alpha-1(II) chain

  It provides the principal fibrillar collagen framework of cartilage and is also important in the vitreous and inner ear. Pathogenic variants cause a broad type II collagenopathy spectrum including Stickler syndrome, spondyloepiphyseal dysplasia, and severe skeletal dysplasias.

  15 ClinVar pathogenic / likely pathogenic and 10 uncertain variants in COL2A1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• FGFR3: Fibroblast growth factor receptor 3

  It normally restrains growth-plate chondrocyte proliferation while regulating multiple developmental pathways. Activating germline variants cause achondroplasia and related skeletal dysplasias, while somatic activating alterations are common in bladder cancer and some other tumors.

  2 ClinVar pathogenic / likely pathogenic and 3 uncertain variants in FGFR3 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• FLNB: Filamin-B

  It crosslinks actin and organizes cytoskeletal signaling in cartilage, bone, and other tissues during development. Pathogenic variants cause a broad skeletal-dysplasia spectrum including atelosteogenesis, Larsen syndrome, and spondylocarpotarsal syndrome.

  1 ClinVar pathogenic / likely pathogenic and 20 uncertain variants in FLNB have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• WDR19: WD repeat-containing protein 19

  Part of the intraflagellar transport A complex, which moves cargo backward through cilia and helps proteins enter the ciliary compartment. By supporting cilium assembly and receptor trafficking, WDR19 contributes to kidney, retinal, skeletal, and reproductive biology.

  1 ClinVar pathogenic / likely pathogenic and 6 uncertain variants in WDR19 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• FBN1: Fibrillin-1

  Its fibrillin-1 microfibrils provide mechanical support to elastic tissues and regulate local availability of growth factors such as TGF-beta. Pathogenic variants cause Marfan syndrome and related fibrillinopathies affecting the aorta, skeleton, eyes, skin, and lungs.

  1 ClinVar pathogenic / likely pathogenic and 3 uncertain variants in FBN1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• SMAD3: SMAD family member 3

  It carries TGF-beta receptor signals into the nucleus to control extracellular-matrix, differentiation, and growth programs. Heterozygous loss-of-function variants cause Loeys-Dietz syndrome type 3 with arterial aneurysm and dissection risk and often early osteoarthritis.

  1 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in SMAD3 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• HSPG2: Basement membrane-specific heparan sulfate proteoglycan core protein

  Perlecan, a major heparan-sulfate proteoglycan in basement membranes. It helps organize the extracellular matrix and supports tissues including cartilage, muscle, and blood vessels.

  0 ClinVar pathogenic / likely pathogenic and 23 uncertain variants in HSPG2 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• MYH11: Myosin-11

  Its smooth-muscle myosin motor generates contractile force in arteries and visceral organs. Pathogenic variants can impair aortic smooth-muscle mechanics and cause familial thoracic aortic aneurysm and dissection, sometimes with patent ductus arteriosus.

  0 ClinVar pathogenic / likely pathogenic and 17 uncertain variants in MYH11 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• NOTCH1: Neurogenic locus notch homolog protein 1

  Ligand-dependent cleavage releases an intracellular domain that directly controls transcriptional programs governing cell fate and differentiation. Pathogenic variants can cause congenital aortic-valve disease and left-sided heart defects, while activating or inactivating somatic changes contribute to several cancers.

  0 ClinVar pathogenic / likely pathogenic and 12 uncertain variants in NOTCH1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• MYLK: Myosin light chain kinase, smooth muscle

  It phosphorylates myosin regulatory light chains to initiate smooth-muscle contraction in blood vessels and visceral tissues. Pathogenic loss-of-function variants can reduce arterial contractile integrity and cause familial thoracic aortic aneurysm and dissection.

  0 ClinVar pathogenic / likely pathogenic and 14 uncertain variants in MYLK have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• COL5A1: Collagen alpha-1(V) chain

  It helps nucleate and regulate type I collagen fibril assembly, controlling fibril diameter and connective-tissue architecture. Haploinsufficiency or structural variants are a major cause of classical Ehlers-Danlos syndrome, with skin hyperextensibility, atrophic scarring, and joint hypermobility.

  0 ClinVar pathogenic / likely pathogenic and 9 uncertain variants in COL5A1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• COL5A2: Collagen alpha-2(V) chain

  It partners with COL5A1-derived chains to regulate collagen fibril formation in skin, tendons, and other connective tissues. Pathogenic variants can cause classical Ehlers-Danlos syndrome with tissue fragility, hyperextensible skin, and joint hypermobility.

  0 ClinVar pathogenic / likely pathogenic and 10 uncertain variants in COL5A2 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• COL1A1: Collagen alpha-1(I) chain

  The alpha-1 chain of type I collagen, the main fibrillar collagen in connective tissue, bone, and skin. Together with its partner chain, it forms strong extracellular fibers, and COL1A1 variants are associated with osteogenesis imperfecta and several Ehlers-Danlos syndromes.

  0 ClinVar pathogenic / likely pathogenic and 10 uncertain variants in COL1A1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• LBR: Delta(14)-sterol reductase LBR

  An inner nuclear-membrane protein with sterol-reductase activity in the cholesterol-biosynthesis pathway. It also contributes to nuclear-envelope organization and myeloid-cell maturation, and LBR variants are associated with Pelger-Huet anomaly and skeletal dysplasia.

  0 ClinVar pathogenic / likely pathogenic and 7 uncertain variants in LBR have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• COL1A2: Collagen alpha-2(I) chain

  It contributes one of the three chains of type I collagen, providing tensile strength to bone, skin, tendon, blood vessels, and other connective tissues. Pathogenic variants can cause osteogenesis imperfecta, Ehlers-Danlos phenotypes, and related connective-tissue disorders.

  0 ClinVar pathogenic / likely pathogenic and 6 uncertain variants in COL1A2 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• PTH1R: Parathyroid hormone/parathyroid hormone-related peptide receptor

  It responds to parathyroid hormone and PTH-related peptide to coordinate calcium homeostasis and growth-plate development through cyclic-AMP and other pathways. Gain- and loss-of-function variants cause distinct skeletal disorders including Jansen metaphyseal chondrodysplasia and Blomstrand chondrodysplasia.

  0 ClinVar pathogenic / likely pathogenic and 3 uncertain variants in PTH1R have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• COL3A1: Collagen alpha-1(III) chain

  Its type III collagen fibrils provide tensile support in arteries, bowel, uterus, skin, and other distensible connective tissues. Pathogenic variants cause vascular Ehlers-Danlos syndrome with marked arterial and hollow-organ fragility.

  0 ClinVar pathogenic / likely pathogenic and 4 uncertain variants in COL3A1 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• FLNA: Filamin-A

  It crosslinks actin and connects the cytoskeleton to membrane receptors and signaling proteins during cell migration and tissue morphogenesis. Pathogenic variants cause a broad spectrum including periventricular nodular heterotopia and several skeletal or connective-tissue disorders.

  0 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in FLNA have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

• SOX9: Transcription factor SOX-9

  It controls chondrocyte differentiation, cartilage formation, and testis development and also regulates multiple organ-specific developmental programs. Haploinsufficiency causes campomelic dysplasia, often with severe skeletal abnormalities and 46,XY sex reversal.

  0 ClinVar pathogenic / likely pathogenic and 2 uncertain variants in SOX9 have source records linked to Connective tissue disease. Association strength is not clinical gene validity.

Weakly linked (only a few uncertain records): TGFBR2, PRKG1, ACTA2, FBN2, LOX, PKD1 and TGFBR1.

ClinVar pathogenic and likely pathogenic variants linked to Connective tissue disease

Which prediction tools work for Connective tissue disease

Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.

• AlphaMissense: 99 out of 100
• MetaLR: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 96 out of 100
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 88 out of 100

Same protein, different disease

• Spondyloepiphyseal dysplasia congenita also has ClinVar records linked to COL2A1 variants; they fall mostly in different places as the Connective tissue disease variants (38 pathogenic / likely pathogenic).
• Achondrogenesis type II also has ClinVar records linked to COL2A1 variants; they fall mostly in different places as the Connective tissue disease variants (34 pathogenic / likely pathogenic).
• Stickler syndrome also has ClinVar records linked to COL2A1 variants; they fall mostly in different places as the Connective tissue disease variants (26 pathogenic / likely pathogenic).
• Spondyloepimetaphyseal dysplasia, Strudwick type also has ClinVar records linked to COL2A1 variants; they fall mostly in different places as the Connective tissue disease variants (18 pathogenic / likely pathogenic).
• Type 2 collagenopathy also has ClinVar records linked to COL2A1 variants; they fall mostly in different places as the Connective tissue disease variants (14 pathogenic / likely pathogenic).
• FGFR3-related chondrodysplasia also has ClinVar records linked to FGFR3 variants; they fall mostly in different places as the Connective tissue disease variants (20 pathogenic / likely pathogenic).
• Hypochondroplasia also has ClinVar records linked to FGFR3 variants; they fall mostly in different places as the Connective tissue disease variants (15 pathogenic / likely pathogenic).
• Achondroplasia also has ClinVar records linked to FGFR3 variants; they fall mostly in different places as the Connective tissue disease variants (9 pathogenic / likely pathogenic).
• Thanatophoric dysplasia also has ClinVar records linked to FGFR3 variants; they fall mostly in different places as the Connective tissue disease variants (8 pathogenic / likely pathogenic).
• Severe achondroplasia - developmental delay - acanthosis nigricans also has ClinVar records linked to FGFR3 variants; they fall mostly in different places as the Connective tissue disease variants (5 pathogenic / likely pathogenic).
• Larsen syndrome also has ClinVar records linked to FLNB variants; they fall mostly in different places as the Connective tissue disease variants (12 pathogenic / likely pathogenic).
• Atelosteogenesis type I also has ClinVar records linked to FLNB variants; they fall mostly in different places as the Connective tissue disease variants (6 pathogenic / likely pathogenic).
• Boomerang dysplasia also has ClinVar records linked to FLNB variants; they fall mostly in different places as the Connective tissue disease variants (3 pathogenic / likely pathogenic).
• Senior-Loken syndrome also has ClinVar records linked to WDR19 variants; they fall mostly in different places as the Connective tissue disease variants (8 pathogenic / likely pathogenic).
• Asphyxiating thoracic dystrophy 5 also has ClinVar records linked to WDR19 variants; they fall mostly in different places as the Connective tissue disease variants (7 pathogenic / likely pathogenic).
• Nephronophthisis also has ClinVar records linked to WDR19 variants; they fall mostly in different places as the Connective tissue disease variants (7 pathogenic / likely pathogenic).
• Spermatogenic failure 72 also has ClinVar records linked to WDR19 variants; they fall mostly in different places as the Connective tissue disease variants (3 pathogenic / likely pathogenic).
• Marfan syndrome also has ClinVar records linked to FBN1 variants; they fall mostly in different places as the Connective tissue disease variants (434 pathogenic / likely pathogenic).
• Familial thoracic aortic aneurysm and aortic dissection also has ClinVar records linked to FBN1 variants; they fall mostly in different places as the Connective tissue disease variants (406 pathogenic / likely pathogenic).
• Isolated thoracic aortic aneurysm also has ClinVar records linked to FBN1 variants; they fall mostly in different places as the Connective tissue disease variants (12 pathogenic / likely pathogenic).
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections also has ClinVar records linked to FBN1 variants; they fall mostly in different places as the Connective tissue disease variants (10 pathogenic / likely pathogenic).
• Acromicric dysplasia also has ClinVar records linked to FBN1 variants; they fall mostly in different places as the Connective tissue disease variants (6 pathogenic / likely pathogenic).
• Familial thoracic aortic aneurysm and aortic dissection also has ClinVar records linked to SMAD3 variants; they fall mostly in different places as the Connective tissue disease variants (28 pathogenic / likely pathogenic).
• Aneurysm-osteoarthritis syndrome also has ClinVar records linked to SMAD3 variants; they fall mostly in different places as the Connective tissue disease variants (18 pathogenic / likely pathogenic).

Diseases related to Connective tissue disease

• Familial thoracic aortic aneurysm and aortic dissection, also linked to COL3A1, COL5A1, COL5A2, FBN1 and 5 more
• Ehlers-Danlos syndrome, also linked to COL1A1, COL1A2, COL3A1, COL5A1 and 2 more
• Ehlers-Danlos syndrome, classic type, 1, also linked to COL1A1, COL1A2, COL5A1 and COL5A2
• Fetal anomalies with a likely genetic cause, also linked to COL1A1, COL2A1 and SOX9
• Osteoporosis, also linked to COL1A1, COL1A2 and PTH1R
• Postmenopausal osteoporosis, also linked to COL1A1, COL1A2 and PTH1R
• Osteogenesis imperfecta, also linked to COL1A1 and COL1A2
• Marfan syndrome, also linked to FBN1 and SMAD3
• Osteogenesis imperfecta, perinatal lethal, also linked to COL1A1 and COL1A2
• Osteogenesis imperfecta with normal sclerae, dominant form, also linked to COL1A1 and COL1A2
• Aortic aneurysm, familial thoracic 7, also linked to MYH11 and MYLK
• Ehlers-Danlos syndrome, arthrochalasia type, also linked to COL1A1 and COL1A2

Frequently asked questions

Which genes have records linked to Connective tissue disease?

This view contains 19 analyzed proteins: COL2A1, FGFR3, FLNB, WDR19, FBN1 and 14 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.

What do the clinical classifications mean?

Linked records include 21 pathogenic or likely pathogenic variants, 62 variants of uncertain significance and 104 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.

Does the evidence score change a VUS classification?

No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.

Can I download the variant evidence?

Download the CSV for all 267 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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