Osteogenesis imperfecta type 4
diseaseOn this page
Also known as common variable OI with normal scleraeOI type 4OI type IVOI4osteogenesis imperfecta type IV
Summary
Osteogenesis imperfecta type 4 (MONDO:0008148) is a disease caused by COL1A1 (GenCC Definitive), with 10 cohort genes and 1 clinical trial. The dominant Reactome pathway is Collagen biosynthesis and modifying enzymes (4 cohort genes). Top therapeutic interventions include cholecalciferol and setrusumab.
At a glance
- Prevalence: 1-9 / 100 000 (Sweden) [Orphanet-validated]
- Causal gene: COL1A1 (GenCC Definitive)
- Cohort genes: 10
- ClinVar variants: 307
- Clinical trials: 1
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Prevalence at birth | 1-9 / 100 000 | 1.35 | Sweden | Validated |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | osteogenesis imperfecta type 4 |
| Mondo ID | MONDO:0008148 |
| MeSH | C536045 |
| OMIM | 166220 |
| Orphanet | 216820 |
| DOID | DOID:0110340 |
| ICD-11 | 829297901 |
| NCIT | C98576 |
| SNOMED CT | 205497004 |
| UMLS | C0268363 |
| MedGen | 78665 |
| GARD | 0008696 |
| Is cancer (heuristic) | no |
Also known as: common variable OI with normal sclerae · OI type 4 · OI type IV · OI4 · osteogenesis imperfecta type IV
Data availability: 307 ClinVar variants · 11 GenCC gene-disease records · 57 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 4
Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, 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
307 retrieved; paginated sample, class counts are floors:
123 pathogenic, 59 pathogenic/likely pathogenic, 47 likely pathogenic, 25 conflicting classifications of pathogenicity, 21 uncertain significance, 15 benign/likely benign, 14 benign, 2 likely benign, 1 not provided
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1072588 | NM_000088.4(COL1A1):c.958-1G>A | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1074344 | NM_000088.4(COL1A1):c.1804G>T (p.Gly602Ter) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1076006 | NM_000088.4(COL1A1):c.288del (p.Asp97fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1192753 | NM_000088.4(COL1A1):c.3656A>G (p.Asp1219Gly) | COL1A1 | Pathogenic/Likely 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 |
| 1342741 | NM_000088.4(COL1A1):c.1444G>A (p.Gly482Arg) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1357973 | NM_000088.4(COL1A1):c.432del (p.Gly145fs) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1382447 | NM_000088.4(COL1A1):c.779G>A (p.Gly260Asp) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1431075 | NM_000088.4(COL1A1):c.1876-2A>G | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1431093 | NM_000088.4(COL1A1):c.1667del (p.Pro556fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1685271 | NM_000088.4(COL1A1):c.608G>A (p.Gly203Asp) | 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 |
| 17286 | NM_000088.4(COL1A1):c.1057G>T (p.Gly353Cys) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 17288 | NM_000088.4(COL1A1):c.2110G>T (p.Gly704Cys) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 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 |
| 17331 | NM_000088.4(COL1A1):c.2515G>A (p.Gly839Ser) | COL1A1 | Pathogenic | no assertion criteria provided |
| 17341 | NM_000088.4(COL1A1):c.642+1G>A | COL1A1 | Pathogenic | no assertion criteria provided |
| 17343 | NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys) | COL1A1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 17345 | NM_000088.4(COL1A1):c.1845_1847del (p.Glu615_Ala616delinsAsp) | COL1A1 | Pathogenic | no assertion criteria provided |
| 17346 | NM_000088.4(COL1A1):c.1299+1G>C | COL1A1 | Pathogenic | no assertion criteria provided |
| 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 |
| 2159543 | NM_000088.4(COL1A1):c.3155G>C (p.Gly1052Ala) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 236248 | NM_000088.4(COL1A1):c.2775del (p.Gly926fs) | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2444032 | NM_000088.4(COL1A1):c.423del (p.Gly142fs) | COL1A1 | Pathogenic | criteria provided, single submitter |
| 2504977 | NM_000088.4(COL1A1):c.750+1G>A | COL1A1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2572450 | NM_000088.4(COL1A1):c.1631del (p.Pro544fs) | COL1A1 | Pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 89 · Orphanet: 38 · 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 |
| WNT1 | Definitive | Autosomal recessive | osteogenesis imperfecta type 15 | 8 |
| 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 |
| SP7 | Strong | Autosomal recessive | osteogenesis imperfecta type 12 | 4 |
| SPARC | Strong | Autosomal recessive | osteogenesis imperfecta type 17 | 6 |
| TMEM38B | Strong | Autosomal recessive | osteogenesis imperfecta type 14 | 3 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| FKBP10 | Orphanet:1149 | Kuskokwim syndrome |
| FKBP10 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| FKBP10 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| FKBP10 | Orphanet:2771 | Bruck syndrome |
| 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 |
| SPARC | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| WNT1 | Orphanet:216812 | Osteogenesis imperfecta type 3 |
| WNT1 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| WNT1 | Orphanet:85193 | Idiopathic juvenile osteoporosis |
| SP7 | Orphanet:1513 | Craniodiaphyseal dysplasia |
| SP7 | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| 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 |
| TMEM38B | Orphanet:216820 | Osteogenesis imperfecta type 4 |
| 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 |
Cohort genes → proteins
10 cohort genes, 10 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 10 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| FKBP10 | HGNC:18169 | ENSG00000141756 | Q96AY3 | Peptidyl-prolyl cis-trans isomerase FKBP10 | 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 |
| SPARC | HGNC:11219 | ENSG00000113140 | P09486 | SPARC | gencc |
| WNT1 | HGNC:12774 | ENSG00000125084 | P04628 | Proto-oncogene Wnt-1 | gencc |
| SP7 | HGNC:17321 | ENSG00000170374 | Q8TDD2 | Transcription factor Sp7 | gencc |
| CRTAP | HGNC:2379 | ENSG00000170275 | O75718 | Cartilage-associated protein | gencc |
| TMEM38B | HGNC:25535 | ENSG00000095209 | Q9NVV0 | Trimeric intracellular cation channel type B | gencc |
| SERPINF1 | HGNC:8824 | ENSG00000132386 | P36955 | Pigment epithelium-derived factor | gencc |
| PPIB | HGNC:9255 | ENSG00000166794 | P23284 | Peptidyl-prolyl cis-trans isomerase B | gencc |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| FKBP10 | Peptidyl-prolyl cis-trans isomerase FKBP10 | PPIases accelerate the folding of proteins during protein synthesis. |
| 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). |
| SPARC | SPARC | Appears to regulate cell growth through interactions with the extracellular matrix and cytokines. |
| WNT1 | Proto-oncogene Wnt-1 | Ligand for members of the frizzled family of seven transmembrane receptors. |
| SP7 | Transcription factor Sp7 | Transcriptional activator essential for osteoblast differentiation. |
| CRTAP | Cartilage-associated protein | Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues. |
| TMEM38B | Trimeric intracellular cation channel type B | Intracellular monovalent cation channel required for maintenance of rapid intracellular calcium release. |
| 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. |
Protein-family classification
Druggable: 1 · Difficult: 1 · Unknown: 8 · Druggable fraction: 0.1
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 | 8 | 1.4× | 0.327 |
| Enzyme (other) | 1 | 1.2× | 0.725 |
| Transcription factor | 1 | 0.8× | 0.725 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| FKBP10 | Other/Unknown | no | PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair | |
| COL1A1 | Other/Unknown | no | Fib_collagen_C, VWF_dom, Collagen | |
| COL1A2 | Other/Unknown | no | Fib_collagen_C, Collagen, Collagen_superfamily | |
| SPARC | Other/Unknown | no | Osteonectin_CS, Kazal_dom, Fol_N | |
| WNT1 | Other/Unknown | no | Wnt, Wnt1, Wnt_CS | |
| SP7 | Transcription factor | no | Znf_C2H2_type, Znf_C2H2_sf | |
| CRTAP | Other/Unknown | no | TPR-like_helical_dom_sf, Collagen_mod_leprecan, Leprecan_dom | |
| TMEM38B | Other/Unknown | no | TRIC_channel | |
| 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 |
Expression context
Cohort genes with no expression data: 0.
8 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) | 10 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| stromal cell of endometrium | 6 |
| periodontal ligament | 3 |
| skin of hip | 2 |
| tibia | 2 |
| endocervix | 2 |
| ascending aorta | 1 |
| thoracic aorta | 1 |
| granulocyte | 1 |
| nucleus accumbens | 1 |
| superior frontal gyrus | 1 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| primordial germ cell in gonad | 1 |
| tendon of biceps brachii | 1 |
| biceps brachii | 1 |
| skeletal muscle tissue of rectus abdominis | 1 |
| sperm | 1 |
| pericardium | 1 |
| pigmented layer of retina | 1 |
| caput epididymis | 1 |
| corpus epididymis | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| FKBP10 | 179 | ubiquitous | marker | stromal cell of endometrium, ascending aorta, thoracic aorta |
| 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 |
| SPARC | 306 | ubiquitous | marker | tibia, stromal cell of endometrium, periodontal ligament |
| WNT1 | 73 | tissue_specific | yes | granulocyte, nucleus accumbens, superior frontal gyrus |
| SP7 | 46 | tissue_specific | yes | primordial germ cell in gonad, tibia, male germ line stem cell (sensu Vertebrata) in testis |
| CRTAP | 288 | ubiquitous | marker | tendon of biceps brachii, stromal cell of endometrium, endocervix |
| TMEM38B | 264 | ubiquitous | marker | sperm, biceps brachii, skeletal muscle tissue of rectus abdominis |
| SERPINF1 | 280 | ubiquitous | marker | pigmented layer of retina, pericardium, endocervix |
| PPIB | 295 | ubiquitous | marker | stromal cell of endometrium, corpus epididymis, caput epididymis |
Protein interactions among cohort
Intra-cohort edges: 17.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| COL1A1 | 5,341 |
| PPIB | 4,718 |
| FKBP10 | 3,473 |
| SPARC | 3,105 |
| WNT1 | 2,506 |
| SP7 | 2,310 |
| SERPINF1 | 1,809 |
| CRTAP | 951 |
| TMEM38B | 839 |
| COL1A2 | 179 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| COL1A1 | COL1A2 | intact |
| COL1A1 | CRTAP | intact, string_interaction |
| COL1A1 | FKBP10 | intact |
| COL1A1 | PPIB | intact, string_interaction |
| COL1A1 | SP7 | string_interaction |
| COL1A1 | SPARC | intact |
| CRTAP | FKBP10 | string_interaction |
| CRTAP | PPIB | string_interaction |
| CRTAP | SERPINF1 | string_interaction |
| CRTAP | TMEM38B | string_interaction |
| FKBP10 | PPIB | string_interaction |
| FKBP10 | SERPINF1 | string_interaction |
| FKBP10 | TMEM38B | string_interaction |
| PPIB | TMEM38B | string_interaction |
| SERPINF1 | TMEM38B | string_interaction |
| SP7 | TMEM38B | string_interaction |
| TMEM38B | WNT1 | string_interaction |
Structural data
PDB: 6 · AlphaFold-only: 4 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| COL1A1 | P02452 | 14 |
| PPIB | P23284 | 8 |
| CRTAP | O75718 | 6 |
| COL1A2 | P08123 | 5 |
| SPARC | P09486 | 4 |
| SERPINF1 | P36955 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| FKBP10 | Q96AY3 | 89.19 |
| WNT1 | P04628 | 86.53 |
| TMEM38B | Q9NVV0 | 80.17 |
| SP7 | Q8TDD2 | 52.78 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 10 evidence-associated genes (7 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 7 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 | 4 | 97.4× | 2e-06 | COL1A1, COL1A2, CRTAP, PPIB |
| Defective VWF binding to collagen type I | 2 | 1087.6× | 3e-05 | COL1A1, COL1A2 |
| Enhanced cleavage of VWF variant by ADAMTS13 | 2 | 815.7× | 3e-05 | COL1A1, COL1A2 |
| Defective VWF cleavage by ADAMTS13 variant | 2 | 815.7× | 3e-05 | COL1A1, COL1A2 |
| Enhanced binding of GP1BA variant to VWF multimer:collagen | 2 | 466.1× | 6e-05 | COL1A1, COL1A2 |
| Defective binding of VWF variant to GPIb:IX:V | 2 | 466.1× | 6e-05 | COL1A1, COL1A2 |
| ECM proteoglycans | 3 | 64.4× | 7e-05 | COL1A1, COL1A2, SPARC |
| GP1b-IX-V activation signalling | 2 | 271.9× | 1e-04 | COL1A1, COL1A2 |
| Anchoring fibril formation | 2 | 217.5× | 2e-04 | COL1A1, COL1A2 |
| Platelet Adhesion to exposed collagen | 2 | 191.9× | 2e-04 | COL1A1, COL1A2 |
| Scavenging by Class A Receptors | 2 | 171.7× | 2e-04 | COL1A1, COL1A2 |
| Fibronectin matrix formation | 2 | 163.1× | 2e-04 | COL1A1, COL1A2 |
| Crosslinking of collagen fibrils | 2 | 163.1× | 2e-04 | COL1A1, COL1A2 |
| RUNX2 regulates osteoblast differentiation | 2 | 130.5× | 4e-04 | COL1A1, SP7 |
| Platelet Aggregation (Plug Formation) | 2 | 125.5× | 4e-04 | COL1A1, COL1A2 |
| Syndecan interactions | 2 | 120.8× | 4e-04 | COL1A1, COL1A2 |
| MET activates PTK2 signaling | 2 | 108.8× | 4e-04 | COL1A1, COL1A2 |
| GPVI-mediated activation cascade | 2 | 88.2× | 6e-04 | COL1A1, COL1A2 |
| Collagen chain trimerization | 2 | 74.2× | 8e-04 | COL1A1, COL1A2 |
| Developmental Lineage of Pancreatic Ductal Cells | 2 | 65.3× | 0.001 | COL1A1, COL1A2 |
| Assembly of collagen fibrils and other multimeric structures | 2 | 57.2× | 0.001 | COL1A1, COL1A2 |
| Collagen degradation | 2 | 50.2× | 0.002 | COL1A1, COL1A2 |
| Non-integrin membrane-ECM interactions | 2 | 44.1× | 0.002 | COL1A1, COL1A2 |
| Integrin cell surface interactions | 2 | 38.4× | 0.002 | COL1A1, COL1A2 |
| Cell surface interactions at the vascular wall | 2 | 27.2× | 0.005 | COL1A1, COL1A2 |
| Scavenging by Class H Receptors | 1 | 407.9× | 0.005 | SPARC |
| Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell | 2 | 24.9× | 0.005 | COL1A1, COL1A2 |
| RUNX2 regulates bone development | 1 | 116.5× | 0.016 | SP7 |
| Binding and Uptake of Ligands by Scavenger Receptors | 1 | 77.7× | 0.023 | SPARC |
| WNT ligand biogenesis and trafficking | 1 | 60.4× | 0.028 | WNT1 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 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 | 4 | 89.9× | 1e-05 | FKBP10, COL1A1, COL1A2, CRTAP |
| bone development | 3 | 82.9× | 4e-04 | WNT1, TMEM38B, PPIB |
| skin morphogenesis | 2 | 280.9× | 0.001 | COL1A1, COL1A2 |
| negative regulation of cell-substrate adhesion | 2 | 210.7× | 0.001 | COL1A1, WNT1 |
| extracellular matrix assembly | 2 | 187.2× | 0.001 | FKBP10, COL1A2 |
| protein folding | 3 | 31.0× | 0.003 | FKBP10, CRTAP, PPIB |
| cerebellum formation | 1 | 1685.2× | 0.006 | WNT1 |
| midbrain-hindbrain boundary maturation during brain development | 1 | 1685.2× | 0.006 | WNT1 |
| protein heterotrimerization | 1 | 1685.2× | 0.006 | COL1A2 |
| cellular response to vitamin E | 1 | 1685.2× | 0.006 | COL1A1 |
| blood vessel development | 2 | 74.9× | 0.006 | COL1A1, COL1A2 |
| cellular response to amino acid stimulus | 2 | 61.3× | 0.006 | COL1A1, COL1A2 |
| bone mineralization | 2 | 54.4× | 0.006 | COL1A2, TMEM38B |
| cellular response to glucose stimulus | 2 | 53.5× | 0.006 | COL1A1, SERPINF1 |
| cellular response to retinoic acid | 2 | 46.8× | 0.008 | COL1A1, SERPINF1 |
| response to insulin | 2 | 46.2× | 0.008 | COL1A1, SP7 |
| diencephalon development | 1 | 842.6× | 0.009 | WNT1 |
| central nervous system morphogenesis | 1 | 842.6× | 0.009 | WNT1 |
| extracellular matrix constituent secretion | 1 | 842.6× | 0.009 | TMEM38B |
| cellular response to fluoride | 1 | 842.6× | 0.009 | COL1A1 |
| tooth mineralization | 1 | 561.7× | 0.010 | COL1A1 |
| astrocyte-dopaminergic neuron signaling | 1 | 561.7× | 0.010 | WNT1 |
| Spemann organizer formation | 1 | 561.7× | 0.010 | WNT1 |
| secretion by lung epithelial cell involved in lung growth | 1 | 561.7× | 0.010 | TMEM38B |
| positive regulation of dermatome development | 1 | 561.7× | 0.010 | WNT1 |
| cellular response to cobalt ion | 1 | 561.7× | 0.010 | SERPINF1 |
| negative regulation of angiogenesis | 2 | 33.7× | 0.010 | SPARC, SERPINF1 |
| forebrain anterior/posterior pattern specification | 1 | 421.3× | 0.012 | WNT1 |
| negative regulation of post-translational protein modification | 1 | 421.3× | 0.012 | CRTAP |
| cell proliferation in midbrain | 1 | 337.0× | 0.013 | WNT1 |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 8
Druggability breadth: 5 of 10 evidence-associated genes (50%) 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 |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| PPIB | 4 | 4 |
| WNT1 | 1 | 1 |
| FKBP10 | 0 | 0 |
| COL1A1 | 0 | 0 |
| COL1A2 | 0 | 0 |
| SPARC | 0 | 0 |
| SP7 | 0 | 0 |
| CRTAP | 0 | 0 |
| TMEM38B | 0 | 0 |
| SERPINF1 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| CYCLOSPORINE | 4 | PPIB |
| ALISPORIVIR | 3 | PPIB |
| SCY 635 | 2 | PPIB |
| NIM811 | 2 | PPIB |
| CIRTUVIVINT | 1 | WNT1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| PPIB | 13 | Binding:13 |
| WNT1 | 10 | Binding:10 |
| COL1A1 | 8 | Binding:8 |
| COL1A2 | 4 | Functional:4 |
| SERPINF1 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| PPIB | 5.2.1.8 | peptidylprolyl isomerase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
5 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 |
| 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) | 1 | PPIB |
| B | Phased (≥1) drug, not yet approved | 1 | WNT1 |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 8 | FKBP10, COL1A1, COL1A2, SPARC, SP7, CRTAP, TMEM38B, SERPINF1 |
Undrugged target profiles
8 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| CRTAP | 0 | PPIB |
| FKBP10 | 0 | — |
| COL1A1 | 8 | — |
| COL1A2 | 4 | — |
| SPARC | 0 | — |
| SP7 | 0 | — |
| TMEM38B | 0 | — |
| SERPINF1 | 1 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 1.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| PHASE2 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03118570 | PHASE2 | COMPLETED | A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804 |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| CHOLECALCIFEROL | 4 | 1 |
| SETRUSUMAB | 3 | 1 |