Osteogenesis imperfecta type 3
diseaseOn this page
Also known as OI type 3OI type IIIOI3osteogenesis imperfecta type IIIosteogenesis imperfecta, progressively deforming with normal scleraeprogressive deforming osteogenesis imperfectaprogressively deforming OIsevere osteogenesis imperfecta
Summary
Osteogenesis imperfecta type 3 (MONDO:0009804) is a disease caused by variants in COL1A1 and COL1A2, with 15 cohort genes and 3 clinical trials. The dominant Reactome pathway is Collagen biosynthesis and modifying enzymes (9 cohort genes). Top therapeutic interventions include cholecalciferol and setrusumab.
At a glance
- Prevalence: 1-9 / 1 000 000 (Sweden) [Orphanet-validated]
- Causal genes: COL1A1 (GenCC Strong), COL1A2 (GenCC Strong)
- Cohort genes: 15
- ClinVar variants: 266
- Clinical trials: 3
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Prevalence at birth | 1-9 / 1 000 000 | 0.89 | Sweden | Validated |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | osteogenesis imperfecta type 3 |
| Mondo ID | MONDO:0009804 |
| MeSH | C536044 |
| OMIM | 259420 |
| Orphanet | 216812 |
| DOID | DOID:0110339 |
| ICD-11 | 629873920 |
| NCIT | C99002 |
| SNOMED CT | 385483009 |
| UMLS | C0268362 |
| MedGen | 78664 |
| GARD | 0008695 |
| Is cancer (heuristic) | no |
Also known as: OI type 3 · OI type III · OI3 · osteogenesis imperfecta type 3 · osteogenesis imperfecta type III · osteogenesis imperfecta, progressively deforming with normal sclerae · progressive deforming osteogenesis imperfecta · progressively deforming OI · severe osteogenesis imperfecta
Data availability: 266 ClinVar variants · 13 GenCC gene-disease records · 3 cell lines.
Disease family
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › osteogenesis imperfecta type 3
Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, short stature-optic atrophy-Pelger-Huët anomaly syndrome, osteogenesis imperfecta type 14, osteogenesis imperfecta type 15, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18, osteogenesis imperfecta, type 19
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
266 retrieved; paginated sample, class counts are floors:
95 pathogenic, 45 likely pathogenic, 44 pathogenic/likely pathogenic, 27 conflicting classifications of pathogenicity, 25 uncertain significance, 14 benign/likely benign, 14 benign, 2 likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1072429 | NM_000088.4(COL1A1):c.2101G>A (p.Gly701Ser) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1076006 | NM_000088.4(COL1A1):c.288del (p.Asp97fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1254747 | NM_000088.4(COL1A1):c.1177C>T (p.Gln393Ter) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1322116 | NM_000088.4(COL1A1):c.1561G>T (p.Gly521Ter) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1342741 | NM_000088.4(COL1A1):c.1444G>A (p.Gly482Arg) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1343415 | NM_000088.4(COL1A1):c.3064G>T (p.Gly1022Cys) | COL1A1 | Pathogenic | no assertion criteria provided |
| 1364729 | NM_000088.4(COL1A1):c.1471G>A (p.Gly491Ser) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1431093 | NM_000088.4(COL1A1):c.1667del (p.Pro556fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1687168 | NM_000088.4(COL1A1):c.104-2A>G | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1687324 | NM_000088.4(COL1A1):c.4159G>A (p.Ala1387Thr) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 17288 | NM_000088.4(COL1A1):c.2110G>T (p.Gly704Cys) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 17296 | NM_000088.4(COL1A1):c.3064G>A (p.Gly1022Ser) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 17303 | COL1A1, EX22DEL | COL1A1 | Pathogenic | no assertion criteria provided |
| 17312 | NM_000088.4(COL1A1):c.994G>A (p.Gly332Arg) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 17313 | NM_000088.4(COL1A1):c.3541G>A (p.Gly1181Ser) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 17322 | NM_000088.4(COL1A1):c.3235G>A (p.Gly1079Ser) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 17324 | NM_000088.4(COL1A1):c.1588G>A (p.Gly530Ser) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 17330 | NM_000088.4(COL1A1):c.3118G>A (p.Gly1040Ser) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 17331 | NM_000088.4(COL1A1):c.2515G>A (p.Gly839Ser) | COL1A1 | Pathogenic | no assertion criteria provided |
| 17332 | NM_000088.4(COL1A1):c.4391T>C (p.Leu1464Pro) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 17336 | NM_000088.4(COL1A1):c.2341_2451+60del | COL1A1 | Pathogenic | no assertion criteria provided |
| 17337 | NM_000088.4(COL1A1):c.3421C>T (p.Arg1141Ter) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 17343 | NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 17347 | NM_000088.4(COL1A1):c.3040C>T (p.Arg1014Cys) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1805989 | NM_000088.4(COL1A1):c.3540del (p.Gly1181fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 265433 | NM_000088.4(COL1A1):c.1678G>A (p.Gly560Ser) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 265435 | NM_000088.4(COL1A1):c.757C>T (p.Arg253Ter) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2772795 | NM_000088.4(COL1A1):c.2597del (p.Gly866fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2780397 | NM_000088.4(COL1A1):c.598G>A (p.Gly200Ser) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 287320 | NM_000088.4(COL1A1):c.2089C>T (p.Arg697Ter) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 93 · Orphanet: 51 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| COL1A1 | Definitive | Autosomal dominant | osteogenesis imperfecta type 4 | 20 |
| COL1A2 | Definitive | Autosomal dominant | osteogenesis imperfecta | 21 |
| P3H1 | Definitive | Autosomal recessive | osteogenesis imperfecta type 8 | 5 |
| WNT1 | Definitive | Autosomal recessive | osteogenesis imperfecta type 15 | 8 |
| BMP1 | Strong | Autosomal recessive | osteogenesis imperfecta type 13 | 5 |
| CREB3L1 | Strong | Autosomal recessive | osteogenesis imperfecta type 16 | 3 |
| CRTAP | Strong | Autosomal recessive | osteogenesis imperfecta type 7 | 5 |
| FKBP10 | Strong | Autosomal recessive | osteogenesis imperfecta type 11 | 11 |
| PPIB | Strong | Autosomal recessive | osteogenesis imperfecta type 9 | 6 |
| SERPINF1 | Strong | Autosomal recessive | osteogenesis imperfecta type 6 | 5 |
| SERPINH1 | Strong | Autosomal recessive | osteogenesis imperfecta type 10 | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| BMP1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| BMP1 | Orphanet:314029 | High bone mass osteogenesis imperfecta |
| WNT1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| WNT1 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| WNT1 | Orphanet:85193 | Idiopathic juvenile osteoporosis |
| FKBP10 | Orphanet:1149 | Kuskokwim syndrome |
| FKBP10 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| FKBP10 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| FKBP10 | Orphanet:2771 | Bruck syndrome |
| P3H1 | Orphanet:216804 | Osteogenesis imperfecta type 2 |
| P3H1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| COL1A1 | Orphanet:1310 | Caffey disease |
| COL1A1 | Orphanet:1899 | Arthrochalasia Ehlers-Danlos syndrome |
| COL1A1 | Orphanet:216796 | Osteogenesis imperfecta type 1 |
| COL1A1 | Orphanet:216804 | Osteogenesis imperfecta type 2 |
| COL1A1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| COL1A1 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| COL1A1 | Orphanet:230857 | Ehlers-Danlos/osteogenesis imperfecta syndrome |
| COL1A1 | Orphanet:287 | Classical Ehlers-Danlos syndrome |
| COL1A1 | Orphanet:31112 | Dermatofibrosarcoma protuberans |
| COL1A1 | Orphanet:314029 | High bone mass osteogenesis imperfecta |
| COL1A2 | Orphanet:1899 | Arthrochalasia Ehlers-Danlos syndrome |
| COL1A2 | Orphanet:216796 | Osteogenesis imperfecta type 1 |
| COL1A2 | Orphanet:216804 | Osteogenesis imperfecta type 2 |
| COL1A2 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| COL1A2 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| COL1A2 | Orphanet:230851 | Cardiac-valvular Ehlers-Danlos syndrome |
| COL1A2 | Orphanet:230857 | Ehlers-Danlos/osteogenesis imperfecta syndrome |
| COL1A2 | Orphanet:314029 | High bone mass osteogenesis imperfecta |
| SERPINF1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| SERPINF1 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| PPIB | Orphanet:216804 | Osteogenesis imperfecta type 2 |
| PPIB | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| PPIB | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| SERPINH1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| CREB3L1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| CREB3L1 | Orphanet:79105 | Myxofibrosarcoma |
| CRTAP | Orphanet:2050 | Cole-Carpenter syndrome |
| CRTAP | Orphanet:216804 | Osteogenesis imperfecta type 2 |
| CRTAP | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| CRTAP | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| SLC34A1 | Orphanet:157215 | Hereditary hypophosphatemic rickets with hypercalciuria |
| SLC34A1 | Orphanet:244305 | Dominant hypophosphatemia with nephrolithiasis or osteoporosis |
| SLC34A1 | Orphanet:300547 | Autosomal recessive infantile hypercalcemia |
| SLC34A1 | Orphanet:3337 | Primary Fanconi renotubular syndrome |
| COL11A1 | Orphanet:2021 | Fibrochondrogenesis |
| COL11A1 | Orphanet:440354 | Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome |
| COL11A1 | Orphanet:560 | Marshall syndrome |
| COL11A1 | Orphanet:90635 | Rare autosomal dominant non-syndromic sensorineural deafness type DFNA |
| COL11A1 | Orphanet:90654 | Stickler syndrome type 2 |
Cohort genes → proteins
15 cohort genes, 15 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 15 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| BMP1 | HGNC:1067 | ENSG00000168487 | P13497 | Bone morphogenetic protein 1 | gencc,clinvar |
| WNT1 | HGNC:12774 | ENSG00000125084 | P04628 | Proto-oncogene Wnt-1 | gencc,clinvar |
| FKBP10 | HGNC:18169 | ENSG00000141756 | Q96AY3 | Peptidyl-prolyl cis-trans isomerase FKBP10 | gencc,clinvar |
| P3H1 | HGNC:19316 | ENSG00000117385 | Q32P28 | Prolyl 3-hydroxylase 1 | gencc,clinvar |
| COL1A1 | HGNC:2197 | ENSG00000108821 | P02452 | Collagen alpha-1(I) chain | gencc,clinvar |
| COL1A2 | HGNC:2198 | ENSG00000164692 | P08123 | Collagen alpha-2(I) chain | gencc,clinvar |
| SERPINF1 | HGNC:8824 | ENSG00000132386 | P36955 | Pigment epithelium-derived factor | gencc,clinvar |
| PPIB | HGNC:9255 | ENSG00000166794 | P23284 | Peptidyl-prolyl cis-trans isomerase B | gencc,clinvar |
| SERPINH1 | HGNC:1546 | ENSG00000149257 | P50454 | Serpin H1 | gencc |
| CREB3L1 | HGNC:18856 | ENSG00000157613 | Q96BA8 | Cyclic AMP-responsive element-binding protein 3-like protein 1 | gencc |
| CRTAP | HGNC:2379 | ENSG00000170275 | O75718 | Cartilage-associated protein | gencc |
| SLC34A1 | HGNC:11019 | ENSG00000131183 | Q06495 | Sodium-dependent phosphate transport protein 2A | clinvar |
| COL11A1 | HGNC:2186 | ENSG00000060718 | P12107 | Collagen alpha-1(XI) chain | clinvar |
| COL5A2 | HGNC:2210 | ENSG00000204262 | P05997 | Collagen alpha-2(V) chain | clinvar |
| KDELR2 | HGNC:6305 | ENSG00000136240 | P33947 | ER lumen protein-retaining receptor 2 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| BMP1 | Bone morphogenetic protein 1 | Metalloprotease that plays key roles in regulating the formation of the extracellular matrix (ECM) via processing of various precursor proteins into mature functional enzymes or structural proteins. |
| WNT1 | Proto-oncogene Wnt-1 | Ligand for members of the frizzled family of seven transmembrane receptors. |
| FKBP10 | Peptidyl-prolyl cis-trans isomerase FKBP10 | PPIases accelerate the folding of proteins during protein synthesis. |
| P3H1 | Prolyl 3-hydroxylase 1 | Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). |
| COL1A1 | Collagen alpha-1(I) chain | Type I collagen is a member of group I collagen (fibrillar forming collagen). |
| COL1A2 | Collagen alpha-2(I) chain | Type I collagen is a member of group I collagen (fibrillar forming collagen). |
| SERPINF1 | Pigment epithelium-derived factor | Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells. |
| PPIB | Peptidyl-prolyl cis-trans isomerase B | PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. |
| SERPINH1 | Serpin H1 | Binds specifically to collagen. |
| CREB3L1 | Cyclic AMP-responsive element-binding protein 3-like protein 1 | Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains… |
| CRTAP | Cartilage-associated protein | Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues. |
| SLC34A1 | Sodium-dependent phosphate transport protein 2A | Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane. |
| COL11A1 | Collagen alpha-1(XI) chain | May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils. |
| COL5A2 | Collagen alpha-2(V) chain | Type V collagen is a member of group I collagen (fibrillar forming collagen). |
| KDELR2 | ER lumen protein-retaining receptor 2 | Membrane receptor that binds the K-D-E-L sequence motif in the C-terminal part of endoplasmic reticulum resident proteins and maintains their localization in that compartment by participating to their vesicle-mediated recycling back from t… |
Protein-family classification
Druggable: 3 · Difficult: 0 · Unknown: 12 · Druggable fraction: 0.2
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Other/Unknown | 12 | 1.4× | 0.145 |
| Protease | 1 | 2.4× | 0.359 |
| Enzyme (other) | 2 | 1.6× | 0.359 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| BMP1 | Protease | yes | 2.7.11.4 | EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom |
| WNT1 | Other/Unknown | no | Wnt, Wnt1, Wnt_CS | |
| FKBP10 | Other/Unknown | no | PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair | |
| P3H1 | Enzyme (other) | yes | 1.14.11.28 | Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, TPR-like_helical_dom_sf |
| COL1A1 | Other/Unknown | no | Fib_collagen_C, VWF_dom, Collagen | |
| COL1A2 | Other/Unknown | no | Fib_collagen_C, Collagen, Collagen_superfamily | |
| SERPINF1 | Other/Unknown | no | Serpin_fam, Serpin_CS, Serpin_dom | |
| PPIB | Enzyme (other) | yes | 5.2.1.8 | Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-like_dom_sf |
| SERPINH1 | Other/Unknown | no | Serpin_fam, Serpin_CS, Serpin_dom | |
| CREB3L1 | Other/Unknown | no | bZIP, bZIP_sf | |
| CRTAP | Other/Unknown | no | TPR-like_helical_dom_sf, Collagen_mod_leprecan, Leprecan_dom | |
| SLC34A1 | Other/Unknown | no | Na/Pi_transpt | |
| COL11A1 | Other/Unknown | no | Fib_collagen_C, Laminin_G, Collagen | |
| COL5A2 | Other/Unknown | no | Fib_collagen_C, VWF_dom, Collagen | |
| KDELR2 | Other/Unknown | no | ER_ret_rcpt |
Expression context
Cohort genes with no expression data: 0.
14 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 15 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| stromal cell of endometrium | 11 |
| periodontal ligament | 4 |
| skin of hip | 2 |
| endocervix | 2 |
| tendon of biceps brachii | 2 |
| tibia | 2 |
| left uterine tube | 1 |
| right adrenal gland cortex | 1 |
| granulocyte | 1 |
| nucleus accumbens | 1 |
| superior frontal gyrus | 1 |
| ascending aorta | 1 |
| thoracic aorta | 1 |
| adenohypophysis | 1 |
| tibial nerve | 1 |
| pericardium | 1 |
| pigmented layer of retina | 1 |
| caput epididymis | 1 |
| corpus epididymis | 1 |
| endometrium epithelium | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| BMP1 | 236 | ubiquitous | marker | stromal cell of endometrium, left uterine tube, right adrenal gland cortex |
| WNT1 | 73 | tissue_specific | yes | granulocyte, nucleus accumbens, superior frontal gyrus |
| FKBP10 | 179 | ubiquitous | marker | stromal cell of endometrium, ascending aorta, thoracic aorta |
| P3H1 | 237 | ubiquitous | marker | stromal cell of endometrium, adenohypophysis, tibial nerve |
| COL1A1 | 298 | ubiquitous | marker | stromal cell of endometrium, skin of hip, periodontal ligament |
| COL1A2 | 295 | ubiquitous | marker | periodontal ligament, stromal cell of endometrium, skin of hip |
| SERPINF1 | 280 | ubiquitous | marker | pigmented layer of retina, pericardium, endocervix |
| PPIB | 295 | ubiquitous | marker | stromal cell of endometrium, corpus epididymis, caput epididymis |
| SERPINH1 | 265 | ubiquitous | marker | stromal cell of endometrium, endometrium epithelium, smooth muscle tissue |
| CREB3L1 | 231 | ubiquitous | marker | nasal cavity epithelium, stromal cell of endometrium, ileal mucosa |
| CRTAP | 288 | ubiquitous | marker | tendon of biceps brachii, stromal cell of endometrium, endocervix |
| SLC34A1 | 52 | tissue_specific | marker | nephron tubule, adult mammalian kidney, kidney epithelium |
| COL11A1 | 209 | broad | marker | tibia, cartilage tissue, periodontal ligament |
| COL5A2 | 266 | ubiquitous | marker | tendon of biceps brachii, periodontal ligament, stromal cell of endometrium |
| KDELR2 | 301 | ubiquitous | marker | stromal cell of endometrium, tibia, mucosa of sigmoid colon |
Protein interactions among cohort
Intra-cohort edges: 24.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| COL1A1 | 5,341 |
| PPIB | 4,718 |
| FKBP10 | 3,473 |
| SLC34A1 | 3,362 |
| WNT1 | 2,506 |
| COL11A1 | 2,433 |
| COL5A2 | 2,286 |
| CREB3L1 | 2,147 |
| BMP1 | 2,003 |
| SERPINF1 | 1,809 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| BMP1 | CRTAP | string_interaction |
| BMP1 | FKBP10 | string_interaction |
| COL11A1 | COL1A1 | string_interaction |
| COL11A1 | COL5A2 | string_interaction |
| COL1A1 | COL1A2 | intact |
| COL1A1 | COL5A2 | string_interaction |
| COL1A1 | CRTAP | intact, string_interaction |
| COL1A1 | FKBP10 | intact |
| COL1A1 | P3H1 | intact, string_interaction |
| COL1A1 | PPIB | intact, string_interaction |
| CREB3L1 | CRTAP | string_interaction |
| CREB3L1 | FKBP10 | string_interaction |
| CREB3L1 | P3H1 | string_interaction |
| CREB3L1 | PPIB | string_interaction |
| CREB3L1 | SERPINF1 | string_interaction |
| CRTAP | FKBP10 | string_interaction |
| CRTAP | P3H1 | biogrid_interaction, intact, string_interaction |
| CRTAP | PPIB | string_interaction |
| CRTAP | SERPINF1 | string_interaction |
| FKBP10 | P3H1 | string_interaction |
| FKBP10 | PPIB | string_interaction |
| FKBP10 | SERPINF1 | string_interaction |
| P3H1 | PPIB | string_interaction |
| P3H1 | SERPINF1 | string_interaction |
Structural data
PDB: 7 · AlphaFold-only: 8 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| COL1A1 | P02452 | 14 |
| BMP1 | P13497 | 8 |
| PPIB | P23284 | 8 |
| P3H1 | Q32P28 | 6 |
| CRTAP | O75718 | 6 |
| COL1A2 | P08123 | 5 |
| SERPINF1 | P36955 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| KDELR2 | P33947 | 93.12 |
| SERPINH1 | P50454 | 91.71 |
| FKBP10 | Q96AY3 | 89.19 |
| WNT1 | P04628 | 86.53 |
| SLC34A1 | Q06495 | 72.24 |
| CREB3L1 | Q96BA8 | 55.66 |
| COL5A2 | P05997 | 53.15 |
| COL11A1 | P12107 | 53.06 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 15 evidence-associated genes (13 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Collagen biosynthesis and modifying enzymes | 9 | 118.0× | 2e-16 | BMP1, P3H1, COL1A1, COL1A2, PPIB, SERPINH1, COL11A1, COL5A2 (+1 more) |
| Assembly of collagen fibrils and other multimeric structures | 5 | 77.1× | 8e-08 | BMP1, COL1A1, COL1A2, COL11A1, COL5A2 |
| MET activates PTK2 signaling | 4 | 117.1× | 5e-07 | COL1A1, COL1A2, COL11A1, COL5A2 |
| Collagen chain trimerization | 4 | 79.9× | 2e-06 | COL1A1, COL1A2, COL11A1, COL5A2 |
| Developmental Lineage of Pancreatic Ductal Cells | 4 | 70.3× | 2e-06 | COL1A1, COL1A2, COL11A1, COL5A2 |
| Anchoring fibril formation | 3 | 175.7× | 5e-06 | BMP1, COL1A1, COL1A2 |
| Collagen degradation | 4 | 54.1× | 5e-06 | COL1A1, COL1A2, COL11A1, COL5A2 |
| Fibronectin matrix formation | 3 | 131.8× | 7e-06 | COL1A1, COL1A2, COL5A2 |
| Crosslinking of collagen fibrils | 3 | 131.8× | 7e-06 | BMP1, COL1A1, COL1A2 |
| Non-integrin membrane-ECM interactions | 4 | 47.5× | 7e-06 | COL1A1, COL1A2, COL11A1, COL5A2 |
| Defective VWF binding to collagen type I | 2 | 585.6× | 2e-05 | COL1A1, COL1A2 |
| Syndecan interactions | 3 | 97.6× | 2e-05 | COL1A1, COL1A2, COL5A2 |
| Enhanced cleavage of VWF variant by ADAMTS13 | 2 | 439.2× | 3e-05 | COL1A1, COL1A2 |
| Defective VWF cleavage by ADAMTS13 variant | 2 | 439.2× | 3e-05 | COL1A1, COL1A2 |
| Enhanced binding of GP1BA variant to VWF multimer:collagen | 2 | 251.0× | 8e-05 | COL1A1, COL1A2 |
| Defective binding of VWF variant to GPIb:IX:V | 2 | 251.0× | 8e-05 | COL1A1, COL1A2 |
| GP1b-IX-V activation signalling | 2 | 146.4× | 2e-04 | COL1A1, COL1A2 |
| ECM proteoglycans | 3 | 34.7× | 2e-04 | COL1A1, COL1A2, COL5A2 |
| Integrin cell surface interactions | 3 | 31.0× | 3e-04 | COL1A1, COL1A2, COL5A2 |
| Platelet Adhesion to exposed collagen | 2 | 103.3× | 4e-04 | COL1A1, COL1A2 |
| Scavenging by Class A Receptors | 2 | 92.5× | 5e-04 | COL1A1, COL1A2 |
| Collagen formation | 2 | 70.3× | 8e-04 | BMP1, SERPINH1 |
| Platelet Aggregation (Plug Formation) | 2 | 67.6× | 9e-04 | COL1A1, COL1A2 |
| GPVI-mediated activation cascade | 2 | 47.5× | 0.002 | COL1A1, COL1A2 |
| Defective SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1) | 1 | 439.2× | 0.005 | SLC34A1 |
| Type II Na+/Pi cotransporters | 1 | 219.6× | 0.009 | SLC34A1 |
| Cell surface interactions at the vascular wall | 2 | 14.6× | 0.015 | COL1A1, COL1A2 |
| HDL assembly | 1 | 109.8× | 0.017 | BMP1 |
| Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell | 2 | 13.4× | 0.017 | COL1A1, COL1A2 |
| CREB3 factors activate genes | 1 | 97.6× | 0.018 | CREB3L1 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| collagen fibril organization | 9 | 134.8× | 4e-16 | BMP1, FKBP10, P3H1, COL1A1, COL1A2, SERPINH1, COL11A1, COL5A2 (+1 more) |
| negative regulation of post-translational protein modification | 2 | 561.7× | 3e-04 | P3H1, CRTAP |
| skeletal system development | 4 | 33.5× | 3e-04 | BMP1, COL1A1, COL1A2, COL5A2 |
| protein folding | 4 | 27.6× | 5e-04 | FKBP10, P3H1, PPIB, CRTAP |
| cellular response to amino acid stimulus | 3 | 61.3× | 5e-04 | COL1A1, COL1A2, COL5A2 |
| bone development | 3 | 55.2× | 6e-04 | WNT1, P3H1, PPIB |
| skin morphogenesis | 2 | 187.2× | 0.001 | COL1A1, COL1A2 |
| response to peptide | 2 | 149.8× | 0.002 | SERPINF1, SLC34A1 |
| negative regulation of cell-substrate adhesion | 2 | 140.4× | 0.002 | WNT1, COL1A1 |
| collagen metabolic process | 2 | 140.4× | 0.002 | P3H1, COL1A2 |
| collagen biosynthetic process | 2 | 140.4× | 0.002 | COL1A1, SERPINH1 |
| extracellular matrix assembly | 2 | 124.8× | 0.002 | FKBP10, COL1A2 |
| cartilage condensation | 2 | 102.1× | 0.002 | BMP1, COL11A1 |
| cerebellum formation | 1 | 1123.5× | 0.009 | WNT1 |
| midbrain-hindbrain boundary maturation during brain development | 1 | 1123.5× | 0.009 | WNT1 |
| protein heterotrimerization | 1 | 1123.5× | 0.009 | COL1A2 |
| cellular response to vitamin E | 1 | 1123.5× | 0.009 | COL1A1 |
| blood vessel development | 2 | 49.9× | 0.009 | COL1A1, COL1A2 |
| chondrocyte development involved in endochondral bone morphogenesis | 1 | 561.7× | 0.011 | SERPINH1 |
| diencephalon development | 1 | 561.7× | 0.011 | WNT1 |
| central nervous system morphogenesis | 1 | 561.7× | 0.011 | WNT1 |
| indole metabolic process | 1 | 561.7× | 0.011 | SLC34A1 |
| extracellular matrix constituent secretion | 1 | 561.7× | 0.011 | CREB3L1 |
| gentamycin metabolic process | 1 | 561.7× | 0.011 | SLC34A1 |
| arsenate ion transmembrane transport | 1 | 561.7× | 0.011 | SLC34A1 |
| cellular response to fluoride | 1 | 561.7× | 0.011 | COL1A1 |
| negative regulation of endodermal cell differentiation | 1 | 561.7× | 0.011 | COL5A2 |
| positive regulation of phosphate transmembrane transport | 1 | 561.7× | 0.011 | SLC34A1 |
| inner ear morphogenesis | 2 | 40.1× | 0.011 | WNT1, COL11A1 |
| cellular response to glucose stimulus | 2 | 35.7× | 0.011 | COL1A1, SERPINF1 |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 12
Druggability breadth: 11 of 15 evidence-associated genes (73%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| PPIB | CYCLOSPORINE |
| SLC34A1 | SODIUM PHOSPHATE, DIBASIC, ANHYDROUS |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| PPIB | 4 | 4 |
| SLC34A1 | 2 | 4 |
| WNT1 | 1 | 1 |
| BMP1 | 0 | 0 |
| FKBP10 | 0 | 0 |
| P3H1 | 0 | 0 |
| COL1A1 | 0 | 0 |
| COL1A2 | 0 | 0 |
| SERPINF1 | 0 | 0 |
| SERPINH1 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| CYCLOSPORINE | 4 | PPIB |
| SODIUM PHOSPHATE, DIBASIC, ANHYDROUS | 4 | SLC34A1 |
| POTASSIUM PHOSPHATE, MONOBASIC | 4 | SLC34A1 |
| ALISPORIVIR | 3 | PPIB |
| SCY 635 | 2 | PPIB |
| NIM811 | 2 | PPIB |
| CIRTUVIVINT | 1 | WNT1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 3.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| BMP1 | 30 | Binding:29, ADMET:1 |
| PPIB | 13 | Binding:13 |
| WNT1 | 10 | Binding:10 |
| COL1A1 | 8 | Binding:8 |
| SLC34A1 | 8 | Binding:7, Functional:1 |
| COL1A2 | 4 | Functional:4 |
| SERPINF1 | 1 | Binding:1 |
| SERPINH1 | 1 | Binding:1 |
| KDELR2 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| BMP1 | 2.7.11.4, 3.4.24.19, 3.4.24.21 | [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase, procollagen C-endopeptidase, astacin |
| P3H1 | 1.14.11.28, 1.14.11.7 | proline 3-hydroxylase, procollagen-proline 3-dioxygenase |
| PPIB | 5.2.1.8 | peptidylprolyl isomerase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| CYCLOSPORINE | 4 | PPIB |
| SODIUM PHOSPHATE, DIBASIC, ANHYDROUS | 4 | SLC34A1 |
| POTASSIUM PHOSPHATE, MONOBASIC | 4 | SLC34A1 |
| ALISPORIVIR | 3 | PPIB |
| SCY 635 | 2 | PPIB |
| NIM811 | 2 | PPIB |
| CIRTUVIVINT | 1 | WNT1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | PPIB, SLC34A1 |
| B | Phased (≥1) drug, not yet approved | 1 | WNT1 |
| C | Druggable family + PDB, no drug | 2 | BMP1, P3H1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 10 | FKBP10, COL1A1, COL1A2, SERPINF1, SERPINH1, CREB3L1, CRTAP, COL11A1, COL5A2, KDELR2 |
Undrugged target profiles
12 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| P3H1 | 0 | PPIB |
| CRTAP | 0 | PPIB |
| BMP1 | 30 | — |
| FKBP10 | 0 | — |
| COL1A1 | 8 | — |
| COL1A2 | 4 | — |
| SERPINF1 | 1 | — |
| SERPINH1 | 1 | — |
| CREB3L1 | 0 | — |
| COL11A1 | 0 | — |
| COL5A2 | 0 | — |
| KDELR2 | 1 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 3.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| PHASE2 | 1 |
| PHASE1/PHASE2 | 1 |
| PHASE1 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT05559801 | PHASE1/PHASE2 | NOT_YET_RECRUITING | Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI) |
| NCT03118570 | PHASE2 | COMPLETED | A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804 |
| NCT01061099 | PHASE1 | COMPLETED | Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| CHOLECALCIFEROL | 4 | 1 |
| SETRUSUMAB | 3 | 1 |