Ehlers-Danlos syndrome: genes and variants

Genes linked to Ehlers-Danlos syndrome

• 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.

  196 disease-causing and 812 uncertain variants in COL3A1 are linked to Ehlers-Danlos syndrome.

• 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.

  4 disease-causing and 13 uncertain variants in COL1A2 are linked to Ehlers-Danlos syndrome.

• TGFBR2: TGF-beta receptor type-2

  It binds TGF-beta ligands and activates TGFBR1 to initiate canonical and noncanonical signaling. Germline pathogenic variants cause Loeys-Dietz syndrome type 2, while somatic loss can remove growth-suppressive TGF-beta responses in cancer.

  4 disease-causing and 4 uncertain variants in TGFBR2 are linked to Ehlers-Danlos syndrome.

• TGFBR1: TGF-beta receptor type-1

  After activation by the ligand-bound receptor complex, it phosphorylates SMAD2 and SMAD3 to propagate TGF-beta signals. Germline pathogenic variants cause Loeys-Dietz syndrome type 1 with arterial aneurysm and dissection and variable craniofacial or skeletal features.

  1 disease-causing and 8 uncertain variants in TGFBR1 are linked to Ehlers-Danlos syndrome.

• 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 7 uncertain variants in SMAD3 are linked to Ehlers-Danlos syndrome.

• 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 25 uncertain variants in COL5A1 are linked to Ehlers-Danlos syndrome.

• 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 16 uncertain variants in COL5A2 are linked to Ehlers-Danlos syndrome.

• 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 25 uncertain variants in COL1A1 are linked to Ehlers-Danlos syndrome.

• ATP7A: Copper-transporting ATPase 1

  It delivers copper to secretory-pathway enzymes and exports excess copper from cells, making it essential for systemic copper distribution. Loss-of-function variants cause Menkes disease or occipital horn syndrome, while some hypomorphic alleles produce distal motor neuropathy.

  0 disease-causing and 6 uncertain variants in ATP7A are linked to Ehlers-Danlos syndrome.

• TGFB2: Transforming growth factor beta-2 proprotein

  Its secreted signaling regulates extracellular matrix, cell differentiation, proliferation, and cardiovascular development. Haploinsufficiency causes a Loeys-Dietz-spectrum connective-tissue disorder with increased risk of thoracic aortic aneurysm and dissection.

  0 disease-causing and 4 uncertain variants in TGFB2 are linked to Ehlers-Danlos syndrome.

Weakly linked (only a few uncertain records): FBN2, COL6A1, RECQL4 and SMARCA2.

Known disease-causing variants in Ehlers-Danlos syndrome

Showing 60 of 206.

Which prediction tools work for Ehlers-Danlos syndrome

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

• AlphaGenome (regulatory): 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 96 out of 100
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 94 out of 100
• CADD: 93 out of 100
• SIFT: 90 out of 100
• phyloP: 88 out of 100
• AlphaGenome (splicing): 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Familial thoracic aortic aneurysm and aortic dissection is also caused by COL3A1 variants; they fall in the same places as the Ehlers-Danlos syndrome variants (57 disease-causing).
• Osteogenesis imperfecta is also caused by COL1A2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (332 disease-causing).
• Ehlers-Danlos syndrome, classic type, 1 is also caused by COL1A2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (265 disease-causing).
• Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (51 disease-causing).
• Osteogenesis imperfecta, perinatal lethal is also caused by COL1A2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (42 disease-causing).
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 is also caused by COL1A2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (11 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (78 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (49 disease-causing).
• Marfan syndrome is also caused by TGFBR2 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (3 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR1 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (23 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR1 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (23 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by SMAD3 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (28 disease-causing).
• Aneurysm-osteoarthritis syndrome is also caused by SMAD3 variants; they fall mostly in different places as the Ehlers-Danlos syndrome variants (18 disease-causing).

Diseases related to Ehlers-Danlos syndrome

• Familial thoracic aortic aneurysm and aortic dissection, also linked to COL3A1, COL5A1, COL5A2, SMAD3 and 3 more
• Connective tissue disorder, also linked to COL1A1, COL1A2, COL3A1, COL5A1 and 2 more
• Ehlers-Danlos syndrome, classic type, 1, also linked to COL1A1, COL1A2, COL5A1 and COL5A2
• Loeys-Dietz syndrome, also linked to SMAD3, TGFB2, TGFBR1 and TGFBR2
• Osteogenesis imperfecta, also linked to COL1A1 and COL1A2
• Marfan syndrome, also linked to TGFBR1 and TGFBR2
• Osteogenesis imperfecta, perinatal lethal, also linked to COL1A1 and COL1A2
• Osteogenesis imperfecta with normal sclerae, dominant form, also linked to COL1A1 and COL1A2
• 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
• Familial aortopathy, also linked to COL3A1 and TGFBR1
• Osteoporosis, also linked to COL1A1 and COL1A2

Frequently asked questions

Which genes are linked to Ehlers-Danlos syndrome?

In CATVariant, Ehlers-Danlos syndrome is linked to 10 analyzed proteins: COL3A1 (Collagen alpha-1(III) chain), COL1A2 (Collagen alpha-2(I) chain), TGFBR2 (TGF-beta receptor type-2), TGFBR1 (TGF-beta receptor type-1), SMAD3 (SMAD family member 3), COL5A1 (Collagen alpha-1(V) chain) and 4 more.

How many genetic variants are linked to Ehlers-Danlos syndrome?

1,181 variants: 206 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 922 are of uncertain significance or have conflicting reports.

Which uncertain variants in Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 127 disease-causing and 230 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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