Connective tissue disorder: genes and variants

Genes linked to Connective tissue disorder

• 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 disease-causing and 10 uncertain variants in COL2A1 are linked to Connective tissue disorder.

• 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 disease-causing and 3 uncertain variants in FGFR3 are linked to Connective tissue disorder.

• 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 disease-causing and 20 uncertain variants in FLNB are linked to Connective tissue disorder.

• 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 disease-causing and 6 uncertain variants in WDR19 are linked to Connective tissue disorder.

• 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 disease-causing and 3 uncertain variants in FBN1 are linked to Connective tissue disorder.

• 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 disease-causing and 1 uncertain variants in SMAD3 are linked to Connective tissue disorder.

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

  0 disease-causing and 23 uncertain variants in HSPG2 are linked to Connective tissue disorder.

• 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 disease-causing and 17 uncertain variants in MYH11 are linked to Connective tissue disorder.

• 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 disease-causing and 12 uncertain variants in NOTCH1 are linked to Connective tissue disorder.

• 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 disease-causing and 14 uncertain variants in MYLK are linked to Connective tissue disorder.

• 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 disease-causing and 9 uncertain variants in COL5A1 are linked to Connective tissue disorder.

• 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 disease-causing and 10 uncertain variants in COL5A2 are linked to Connective tissue disorder.

• 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 disease-causing and 10 uncertain variants in COL1A1 are linked to Connective tissue disorder.

• 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 disease-causing and 6 uncertain variants in COL1A2 are linked to Connective tissue disorder.

• 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 disease-causing and 7 uncertain variants in LBR are linked to Connective tissue disorder.

• 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 disease-causing and 3 uncertain variants in PTH1R are linked to Connective tissue disorder.

• 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 disease-causing and 4 uncertain variants in COL3A1 are linked to Connective tissue disorder.

• 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 disease-causing and 1 uncertain variants in FLNA are linked to Connective tissue disorder.

• 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 disease-causing and 2 uncertain variants in SOX9 are linked to Connective tissue disorder.

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

Known disease-causing variants in Connective tissue disorder

Which prediction tools work for Connective tissue disorder

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

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

Diseases related to Connective tissue disorder

• 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
• 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
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, also linked to COL1A1 and COL1A2

Frequently asked questions

Which genes are linked to Connective tissue disorder?

In CATVariant, Connective tissue disorder is linked to 19 analyzed proteins: COL2A1 (Collagen alpha-1(II) chain), FGFR3 (Fibroblast growth factor receptor 3), FLNB (Filamin-B), WDR19 (WD repeat-containing protein 19), FBN1 (Fibrillin-1), SMAD3 (SMAD family member 3) and 13 more.

How many genetic variants are linked to Connective tissue disorder?

264 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 166 are of uncertain significance or have conflicting reports.

Which uncertain variants in Connective tissue disorder look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Connective tissue disorder?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 18 disease-causing and 179 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis 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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