Osteogenesis imperfecta: genes and variants
Osteogenesis imperfecta is linked to 4 analyzed proteins (COL1A2, COL1A1, LRP5 and ALPL). 576 DNA variants are known to cause it; 1,020 more are uncertain, and 8 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: osteogenesis imperfecta type 1; osteogenesis imperfecta type 2; osteogenesis imperfecta type 3; osteogenesis imperfecta type 4; Osteogenesis imperfecta type I; Osteogenesis imperfecta type III; OSTEOGENESIS IMPERFECTA, TYPE IIC
Genes linked to Osteogenesis imperfecta
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.
332 disease-causing and 508 uncertain variants in COL1A2 are linked to Osteogenesis imperfecta.
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.
239 disease-causing and 494 uncertain variants in COL1A1 are linked to Osteogenesis imperfecta.
LRP5: Low-density lipoprotein receptor-related protein 5
It transduces canonical Wnt signals that strongly regulate bone formation and also contributes to retinal vascular development. Loss-of-function variants cause osteoporosis-pseudoglioma syndrome, while activating variants cause high-bone-mass disorders.
3 disease-causing and 12 uncertain variants in LRP5 are linked to Osteogenesis imperfecta.
ALPL: Alkaline phosphatase, tissue-nonspecific isozyme
It hydrolyzes extracellular pyrophosphate and other phosphate-containing substrates, enabling normal mineralization of bone and teeth. Loss-of-function variants cause hypophosphatasia, with severity ranging from lethal perinatal skeletal hypomineralization to adult fractures and dental disease.
2 disease-causing and 5 uncertain variants in ALPL are linked to Osteogenesis imperfecta.
Weakly linked (only a few uncertain records): COL5A2.
Known disease-causing variants in Osteogenesis imperfecta
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| COL1A2 G130D | 130 | Disease-causing (★★) | |
| COL1A2 G130V | 130 | Disease-causing (★★) | |
| COL1A2 G193S | 193 | Disease-causing (★★) | |
| COL1A2 G259D | 259 | Disease-causing (★★) | |
| COL1A2 G292S | 292 | Disease-causing (★★) | |
| COL1A2 G337S | 337 | Disease-causing (★★) | |
| COL1A2 G367R | 367 | Disease-causing (★★) | |
| COL1A2 G391S | 391 | Disease-causing (★★) | |
| COL1A2 G400A | 400 | Disease-causing (★★) | |
| COL1A2 G592S | 592 | Disease-causing (★★) | |
| COL1A2 G613R | 613 | Disease-causing (★★) | |
| COL1A2 G613E | 613 | Disease-causing (★★) | |
| COL1A2 G616E | 616 | Disease-causing (★★) | |
| COL1A2 G631D | 631 | Disease-causing (★★) | |
| COL1A2 G631V | 631 | Disease-causing (★★) | |
| COL1A2 G766S | 766 | Disease-causing (★★) | |
| COL1A2 G772S | 772 | Disease-causing (★★) | |
| COL1A2 G1102D | 1102 | Disease-causing (★★) | |
| COL1A1 G182C | 182 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G272C | 272 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G380S | 380 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G476R | 476 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G641R | 641 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G704S | 704 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G857C | 857 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G1022A | 1022 | Triple-helical region | Disease-causing (★★) |
| COL1A2 G277A | 277 | Disease-causing (★★) | |
| COL1A2 G469A | 469 | 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 G700R | 700 | Disease-causing (★★) | |
| COL1A2 G700C | 700 | Disease-causing (★★) | |
| COL1A2 G766R | 766 | Disease-causing (★★) | |
| COL1A2 G766D | 766 | Disease-causing (★★) | |
| COL1A2 G769C | 769 | Disease-causing (★★) | |
| COL1A2 G772R | 772 | Disease-causing (★★) | |
| COL1A2 G775E | 775 | Disease-causing (★★) | |
| COL1A2 G802V | 802 | Disease-causing (★★) | |
| COL1A2 G913S | 913 | Disease-causing (★★) | |
| COL1A2 G919S | 919 | Disease-causing (★★) | |
| ALPL R184W | 184 | Disease-causing (★★) | |
| ALPL F327C | 327 | Disease-causing (★★) | |
| COL1A1 M1I | 1 | Disease-causing (★★) | |
| COL1A1 G197D | 197 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G197C | 197 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G197V | 197 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G203R | 203 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G203D | 203 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G203V | 203 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G215V | 215 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G221D | 221 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G221S | 221 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G224V | 224 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G224S | 224 | Triple-helical region | Disease-causing (★★) |
| COL1A1 G227R | 227 | Triple-helical region | Disease-causing (★★) |
Showing 60 of 576.
Uncertain variants in Osteogenesis imperfecta that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| COL1A2 G694S | 694 | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; G694D at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.973 | |
| 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: 2 other pathogenic changes within 3 positions; G961D at the same position is pathogenic; seen in 3.4e-06 of gnomAD DNA copies; REVEL 0.972 | |
| COL1A2 G904A | 904 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; G904V at the same position is pathogenic; REVEL 0.992 | |
| COL1A1 D1441N | 1441 | Fibrillar collagen NC1 | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; D1441H at the same position is pathogenic; REVEL 0.914 |
| COL1A1 R733H | 733 | Triple-helical region | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R733C at the same position is pathogenic; REVEL 0.911 |
| COL1A1 G1272E | 1272 | Fibrillar collagen NC1 | Uncertain (★) | +6: 3 other pathogenic changes within 3 positions; G1272V at the same position is pathogenic; REVEL 0.877 |
| COL1A1 R312H | 312 | Triple-helical region | Uncertain (★★) | +6: 5 other pathogenic changes within 3 positions; R312C at the same position is pathogenic; REVEL 0.810 |
Which prediction tools work for Osteogenesis imperfecta
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: 99 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)
- AlphaMissense: 96 out of 100
- MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- ESM1b (LLR): 96 out of 100
- PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 91 out of 100
- SIFT: 91 out of 100
- phyloP: 84 out of 100
- AlphaGenome (splicing): 61 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A2 variants; they fall in the same places as the Osteogenesis imperfecta variants (51 disease-causing).
- Osteogenesis imperfecta, perinatal lethal is also caused by COL1A2 variants; they fall in the same places as the Osteogenesis imperfecta 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 Osteogenesis imperfecta variants (11 disease-causing).
- Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A2 variants; they fall in the same places as the Osteogenesis imperfecta variants (7 disease-causing).
- Ehlers-Danlos syndrome, cardiac valvular type is also caused by COL1A2 variants; they fall in the same places as the Osteogenesis imperfecta variants (6 disease-causing).
- Osteogenesis imperfecta, perinatal lethal is also caused by COL1A1 variants; they fall in the same places as the Osteogenesis imperfecta variants (52 disease-causing).
- Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A1 variants; they fall partly in the same places as the Osteogenesis imperfecta variants (34 disease-causing).
- Infantile cortical hyperostosis is also caused by COL1A1 variants; they fall in the same places as the Osteogenesis imperfecta variants (15 disease-causing).
- Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A1 variants; they fall in the same places as the Osteogenesis imperfecta variants (10 disease-causing).
- Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 is also caused by COL1A1 variants; they fall partly in the same places as the Osteogenesis imperfecta variants (6 disease-causing).
- Exudative vitreoretinopathy 4 is also caused by LRP5 variants; they fall mostly in different places as the Osteogenesis imperfecta variants (17 disease-causing).
- Osteoporosis with pseudoglioma is also caused by LRP5 variants; they fall mostly in different places as the Osteogenesis imperfecta variants (9 disease-causing).
- Worth disease is also caused by LRP5 variants; they fall mostly in different places as the Osteogenesis imperfecta variants (9 disease-causing).
- Autosomal dominant osteopetrosis 1 is also caused by LRP5 variants; they fall mostly in different places as the Osteogenesis imperfecta variants (6 disease-causing).
- Polycystic liver disease 4 with or without kidney cysts is also caused by LRP5 variants; they fall mostly in different places as the Osteogenesis imperfecta variants (6 disease-causing).
- Hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Osteogenesis imperfecta variants (172 disease-causing).
- Adult hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Osteogenesis imperfecta variants (113 disease-causing).
- Childhood hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Osteogenesis imperfecta variants (60 disease-causing).
- Infantile hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Osteogenesis imperfecta variants (40 disease-causing).
- Hypophosphataemia or rickets is also caused by ALPL variants; they fall mostly in different places as the Osteogenesis imperfecta variants (8 disease-causing).
Diseases related to Osteogenesis imperfecta
- Osteoporosis, also linked to COL1A1, COL1A2 and LRP5
- Postmenopausal osteoporosis, also linked to COL1A1, COL1A2 and LRP5
- Ehlers-Danlos syndrome, classic type, 1, also linked to COL1A1 and COL1A2
- Ehlers-Danlos syndrome, 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
- Connective tissue disorder, 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
- Skeletal dysplasia, also linked to COL1A2 and LRP5
- Hypophosphatasia, also linked to ALPL
- Adult hypophosphatasia, also linked to ALPL
Frequently asked questions
Which genes are linked to Osteogenesis imperfecta?
In CATVariant, Osteogenesis imperfecta is linked to 4 analyzed proteins: COL1A2 (Collagen alpha-2(I) chain), COL1A1 (Collagen alpha-1(I) chain), LRP5 (Low-density lipoprotein receptor-related protein 5) and ALPL (Alkaline phosphatase, tissue-nonspecific isozyme).
How many genetic variants are linked to Osteogenesis imperfecta?
1,834 variants: 576 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,020 are of uncertain significance or have conflicting reports.
Which uncertain variants in Osteogenesis imperfecta look disease-causing?
8 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL1A2 G694S, COL1A2 G163S, COL1A2 G961V, COL1A2 G904A and COL1A1 D1441N. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Osteogenesis imperfecta?
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 321 disease-causing and 89 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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