Osteoporosis: genes and variants

Genes linked to Osteoporosis

• 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.

  6 disease-causing and 1 uncertain variants in COL1A1 are linked to Osteoporosis.

• 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.

  2 disease-causing and 2 uncertain variants in COL1A2 are linked to Osteoporosis.

• 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.

  0 disease-causing and 26 uncertain variants in LRP5 are linked to Osteoporosis.

• ESR1: Estrogen receptor

  Estrogen binding redirects its transcriptional activity toward programs controlling reproductive, skeletal, metabolic, and mammary physiology. Persistent ESR1 signaling drives most hormone-receptor-positive breast cancers, while acquired activating variants are an important mechanism of endocrine-therapy resistance.

  0 disease-causing and 0 uncertain variants in ESR1 are linked to Osteoporosis.

• 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 0 uncertain variants in PTH1R are linked to Osteoporosis.

• SOST: Sclerostin

  It restrains bone formation by inhibiting canonical Wnt signaling in osteoblast-lineage cells. Loss-of-function variants cause sclerosteosis or van Buchem disease with very high bone mass, while therapeutic neutralization increases bone formation in osteoporosis.

  0 disease-causing and 0 uncertain variants in SOST are linked to Osteoporosis.

• VDR: Vitamin D3 receptor

  It converts active vitamin D binding into transcriptional programs that regulate calcium and phosphate balance, bone mineralization, and many tissue-specific functions. Biallelic loss-of-function variants cause hereditary vitamin-D-resistant rickets with hypocalcemia, secondary hyperparathyroidism, and impaired bone mineralization.

  0 disease-causing and 0 uncertain variants in VDR are linked to Osteoporosis.

Known disease-causing variants in Osteoporosis

Which prediction tools work for Osteoporosis

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Osteogenesis imperfecta is also caused by COL1A1 variants; they fall mostly in different places as the Osteoporosis variants (239 disease-causing).
• Osteogenesis imperfecta, perinatal lethal is also caused by COL1A1 variants; they fall mostly in different places as the Osteoporosis variants (52 disease-causing).
• Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A1 variants; they fall mostly in different places as the Osteoporosis variants (34 disease-causing).
• Infantile cortical hyperostosis is also caused by COL1A1 variants; they fall mostly in different places as the Osteoporosis variants (15 disease-causing).
• Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A1 variants; they fall mostly in different places as the Osteoporosis variants (10 disease-causing).
• Osteogenesis imperfecta is also caused by COL1A2 variants; they fall mostly in different places as the Osteoporosis variants (332 disease-causing).
• Ehlers-Danlos syndrome, classic type, 1 is also caused by COL1A2 variants; they fall mostly in different places as the Osteoporosis 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 Osteoporosis variants (51 disease-causing).
• Osteogenesis imperfecta, perinatal lethal is also caused by COL1A2 variants; they fall mostly in different places as the Osteoporosis 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 Osteoporosis variants (11 disease-causing).

Diseases related to Osteoporosis

• Postmenopausal osteoporosis, also linked to COL1A1, COL1A2, ESR1, LRP5 and 2 more
• Osteogenesis imperfecta, also linked to COL1A1, COL1A2 and LRP5
• Connective tissue disorder, also linked to COL1A1, COL1A2 and PTH1R
• 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
• 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
• Phenylketonuria, also linked to COL1A1
• Exudative vitreoretinopathy 4, also linked to LRP5

Frequently asked questions

Which genes are linked to Osteoporosis?

In CATVariant, Osteoporosis is linked to 7 analyzed proteins: COL1A1 (Collagen alpha-1(I) chain), COL1A2 (Collagen alpha-2(I) chain), LRP5 (Low-density lipoprotein receptor-related protein 5), ESR1 (Estrogen receptor), PTH1R (Parathyroid hormone/parathyroid hormone-related peptide receptor), SOST (Sclerostin) and 1 more.

How many genetic variants are linked to Osteoporosis?

40 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 29 are of uncertain significance or have conflicting reports.

Which uncertain variants in Osteoporosis look disease-causing?

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

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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