Ehlers-Danlos syndrome, classic type, 1: genes and variants
Ehlers-Danlos syndrome, classic type, 1 is linked to 4 analyzed proteins (COL1A2, COL5A1, COL5A2 and COL1A1). 296 DNA variants are known to cause it; 1,980 more are uncertain, and 7 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Ehlers-Danlos syndrome, classic type; Ehlers-Danlos syndrome, classic type, 2
Genes linked to Ehlers-Danlos syndrome, classic type, 1
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.
265 disease-causing and 481 uncertain variants in COL1A2 are linked to Ehlers-Danlos syndrome, classic type, 1.
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.
19 disease-causing and 862 uncertain variants in COL5A1 are linked to Ehlers-Danlos syndrome, classic type, 1.
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.
12 disease-causing and 635 uncertain variants in COL5A2 are linked to Ehlers-Danlos syndrome, classic type, 1.
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 1 uncertain variants in COL1A1 are linked to Ehlers-Danlos syndrome, classic type, 1.
Weakly linked (only a few uncertain records): TGFBR1.
Where Ehlers-Danlos syndrome, classic type, 1 variants cluster
- COL5A1 Fibrillar collagen NC1 (positions 1609–1837): 4 of 19 disease-causing changes, 1.7× more than its size predicts.
Known disease-causing variants in Ehlers-Danlos syndrome, classic type, 1
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| COL1A2 G193S | 193 | Disease-causing (★★) | |
| COL1A2 G280S | 280 | Disease-causing (★★) | |
| COL1A2 G292S | 292 | Disease-causing (★★) | |
| COL1A2 G337S | 337 | Disease-causing (★★) | |
| COL1A2 G391S | 391 | Disease-causing (★★) | |
| COL1A2 G592S | 592 | Disease-causing (★★) | |
| COL1A2 G613R | 613 | Disease-causing (★★) | |
| COL1A2 G613E | 613 | Disease-causing (★★) | |
| COL1A2 G625C | 625 | Disease-causing (★★) | |
| COL1A2 G631D | 631 | Disease-causing (★★) | |
| COL1A2 G631V | 631 | Disease-causing (★★) | |
| COL1A2 G766S | 766 | Disease-causing (★★) | |
| COL1A2 G772S | 772 | Disease-causing (★★) | |
| COL1A2 G277A | 277 | Disease-causing (★★) | |
| COL1A2 G493E | 493 | Disease-causing (★★) | |
| COL1A2 G505S | 505 | Disease-causing (★★) | |
| COL1A2 G598A | 598 | Disease-causing (★★) | |
| COL1A2 G661C | 661 | Disease-causing (★★) | |
| COL1A2 G661R | 661 | Disease-causing (★★) | |
| COL1A2 G664D | 664 | Disease-causing (★★) | |
| COL1A2 G676A | 676 | Disease-causing (★★) | |
| COL1A2 G679S | 679 | Disease-causing (★★) | |
| COL1A2 G700R | 700 | Disease-causing (★★) | |
| COL1A2 G700C | 700 | Disease-causing (★★) | |
| COL1A2 G766R | 766 | Disease-causing (★★) | |
| COL1A2 G769C | 769 | Disease-causing (★★) | |
| COL1A2 G772R | 772 | Disease-causing (★★) | |
| COL1A2 G775E | 775 | Disease-causing (★★) | |
| COL1A2 G913S | 913 | Disease-causing (★★) | |
| COL1A2 G919S | 919 | Disease-causing (★★) | |
| COL1A2 G112V | 112 | Disease-causing (★★) | |
| COL1A2 G118V | 118 | Disease-causing (★★) | |
| COL1A2 G130D | 130 | Disease-causing (★★) | |
| COL1A2 G151R | 151 | Disease-causing (★★) | |
| COL1A2 G190E | 190 | Disease-causing (★★) | |
| COL1A2 G196C | 196 | Disease-causing (★★) | |
| COL1A2 G202D | 202 | Disease-causing (★★) | |
| COL1A2 G205D | 205 | Disease-causing (★★) | |
| COL1A2 G211D | 211 | Disease-causing (★★) | |
| COL1A2 G220D | 220 | Disease-causing (★★) | |
| COL1A2 G247C | 247 | Disease-causing (★★) | |
| COL1A2 G256V | 256 | Disease-causing (★★) | |
| COL1A2 G265V | 265 | Disease-causing (★★) | |
| COL1A2 G265D | 265 | Disease-causing (★★) | |
| COL1A2 G274V | 274 | Disease-causing (★★) | |
| COL1A2 G280C | 280 | Disease-causing (★★) | |
| COL1A2 G286A | 286 | Disease-causing (★★) | |
| COL1A2 G286S | 286 | Disease-causing (★★) | |
| COL1A2 G292R | 292 | Disease-causing (★★) | |
| COL1A2 G292C | 292 | Disease-causing (★★) | |
| COL1A2 G298S | 298 | Disease-causing (★★) | |
| COL1A2 G304S | 304 | Disease-causing (★★) | |
| COL1A2 G319E | 319 | Disease-causing (★★) | |
| COL1A2 G322S | 322 | Disease-causing (★★) | |
| COL1A2 G325R | 325 | Disease-causing (★★) | |
| COL1A2 G349S | 349 | Disease-causing (★★) | |
| COL1A2 G367R | 367 | Disease-causing (★★) | |
| COL1A2 G400A | 400 | Disease-causing (★★) | |
| COL1A2 G601S | 601 | Disease-causing (★★) | |
| COL1A2 G622C | 622 | Disease-causing (★★) |
Showing 60 of 296.
Uncertain variants in Ehlers-Danlos syndrome, classic type, 1 that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| COL1A2 G163S | 163 | Conflicting reports (★) | +7: 3 other pathogenic changes within 3 positions; G163V at the same position is pathogenic; seen in 6.9e-07 of gnomAD DNA copies; REVEL 0.969 | |
| COL1A2 G961V | 961 | Conflicting reports (★) | +7: G961D at the same position is pathogenic; seen in 3.4e-06 of gnomAD DNA copies; REVEL 0.972 | |
| COL5A2 G324S | 324 | Uncertain (★) | +7: G324D at the same position is pathogenic; seen in 6.9e-07 of gnomAD DNA copies; REVEL 0.965 | |
| COL1A2 K264E | 264 | Uncertain (★★) | +7: 6 other pathogenic changes within 3 positions; K264N at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.835 | |
| COL5A1 G478C | 478 | Interrupted collagenous region | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; G478A at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.97 |
| COL5A1 G481V | 481 | Interrupted collagenous region | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; G481R at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.98 |
| COL5A1 G478S | 478 | Interrupted collagenous region | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; G478A at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.97 |
Which prediction tools work for Ehlers-Danlos syndrome, classic type, 1
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- MutPred2: 100 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)
- CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 96 out of 100
- PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 91 out of 100
- phyloP: 90 out of 100
- SIFT: 90 out of 100
Same protein, different disease
- Osteogenesis imperfecta is also caused by COL1A2 variants; they fall in the same places as the Ehlers-Danlos syndrome, classic type, 1 variants (332 disease-causing).
- Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A2 variants; they fall in the same places as the Ehlers-Danlos syndrome, classic type, 1 variants (51 disease-causing).
- Osteogenesis imperfecta, perinatal lethal is also caused by COL1A2 variants; they fall in the same places as the Ehlers-Danlos syndrome, classic type, 1 variants (42 disease-causing).
- Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 is also caused by COL1A2 variants; they fall in the same places as the Ehlers-Danlos syndrome, classic type, 1 variants (11 disease-causing).
- Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A2 variants; they fall in the same places as the Ehlers-Danlos syndrome, classic type, 1 variants (7 disease-causing).
- Familial thoracic aortic aneurysm and aortic dissection is also caused by COL5A1 variants; they fall mostly in different places as the Ehlers-Danlos syndrome, classic type, 1 variants (3 disease-causing).
Diseases related to Ehlers-Danlos syndrome, classic type, 1
- Ehlers-Danlos syndrome, also linked to COL1A1, COL1A2, COL5A1 and COL5A2
- Connective tissue disorder, also linked to COL1A1, COL1A2, COL5A1 and COL5A2
- Familial thoracic aortic aneurysm and aortic dissection, also linked to COL5A1 and COL5A2
- 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
- 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
- Osteoporosis, also linked to COL1A1 and COL1A2
- Postmenopausal osteoporosis, also linked to COL1A1 and COL1A2
- Phenylketonuria, also linked to COL1A1
- Infantile cortical hyperostosis, also linked to COL1A1
Frequently asked questions
Which genes are linked to Ehlers-Danlos syndrome, classic type, 1?
In CATVariant, Ehlers-Danlos syndrome, classic type, 1 is linked to 4 analyzed proteins: COL1A2 (Collagen alpha-2(I) chain), COL5A1 (Collagen alpha-1(V) chain), COL5A2 (Collagen alpha-2(V) chain) and COL1A1 (Collagen alpha-1(I) chain).
How many genetic variants are linked to Ehlers-Danlos syndrome, classic type, 1?
2,629 variants: 296 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,980 are of uncertain significance or have conflicting reports.
Which uncertain variants in Ehlers-Danlos syndrome, classic type, 1 look disease-causing?
7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL1A2 G163S, COL1A2 G961V, COL5A2 G324S, COL1A2 K264E and COL5A1 G478C. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Ehlers-Danlos syndrome, classic type, 1?
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 79 disease-causing and 99 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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