Osteogenesis imperfecta

Summary

Osteogenesis imperfecta (MONDO:0019019) is a disease (an umbrella term covering 10 Mondo subtypes) caused by variants in COL1A2, FKBP10, and KIF5B, with 30 cohort genes and 77 clinical trials. The dominant Reactome pathway is Collagen biosynthesis and modifying enzymes (9 cohort genes). Top therapeutic interventions include alendronic acid, risedronic acid, and pamidronic acid.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal genes: COL1A2 (GenCC Definitive), FKBP10 (GenCC Strong), KIF5B (GenCC Strong)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 30
• ClinVar variants: 911
• Phenotypes (HPO): 114
• Clinical trials: 77

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	8.06	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.375	China	Validated
Prevalence at birth	1-9 / 100 000	6.4	France	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	Latin America	Validated
Prevalence at birth	1-9 / 100 000	1.5	Ireland	Validated
Prevalence at birth	1-9 / 100 000	6.95	United States	Validated
Prevalence at birth	1-9 / 100 000	7.4	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

114 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000410	Mixed hearing impairment	Very frequent (80-99%)
HP:0000444	Convex nasal ridge	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000682	Abnormality of dental enamel	Very frequent (80-99%)
HP:0000768	Pectus carinatum	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000883	Thin ribs	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0002992	Abnormality of tibia morphology	Very frequent (80-99%)
HP:0004331	Decreased skull ossification	Very frequent (80-99%)
HP:0005019	Diaphyseal thickening	Very frequent (80-99%)
HP:0011073	Abnormality of dental color	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000239	Large fontanelles	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0000689	Dental malocclusion	Frequent (30-79%)
HP:0000703	Dentinogenesis imperfecta	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000774	Narrow chest	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000973	Cutis laxa	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001730	Progressive hearing impairment	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0002823	Abnormality of femur morphology	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0002953	Vertebral compression fracture	Frequent (30-79%)
HP:0002980	Femoral bowing	Frequent (30-79%)
HP:0003084	Fractures of the long bones	Frequent (30-79%)
HP:0003100	Slender long bone	Frequent (30-79%)
HP:0003103	Abnormal cortical bone morphology	Frequent (30-79%)
HP:0003272	Abnormality of the hip bone	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	osteogenesis imperfecta
Mondo ID	MONDO:0019019
MeSH	D010013
OMIM	166200
Orphanet	666
DOID	DOID:12347
ICD-10-CM	Q78.0
ICD-11	1219932551
NCIT	C26837
SNOMED CT	78314001
UMLS	C0029434
MedGen	45246
GARD	0001017
MedDRA	10031243
NORD	1535
Is cancer (heuristic)	no

Also known as: brittle bone disease · glass bone disease · Lobstein disease · OI · Osteopsathyrosis · Porak and Durante disease · Vrolik disease

Data availability: 911 ClinVar variants · 8 GenCC gene-disease records · 43 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

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

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, achondroplasia, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia, Spahr type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, Pyle disease, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, acrocapitofemoral dysplasia, brachyolmia, Desbuquois dysplasia, fibrochondrogenesis, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

Subtypes (10): brittle bone disorder, osteogenesis imperfecta type 13, osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome, high bone mass osteogenesis imperfecta, osteogenesis imperfecta, IIA 22, osteogenesis imperfecta, type 21, osteogenesis imperfecta, type 20, COL1A2-related osteogenesis imperfecta, osteogenesis imperfecta and a reduction of bone mineral density., osteogenesis imperfecta, type 23

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

600 retrieved; paginated sample, class counts are floors:

154 conflicting classifications of pathogenicity, 138 uncertain significance, 64 likely pathogenic, 63 pathogenic, 62 benign/likely benign, 62 benign, 50 pathogenic/likely pathogenic, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13664	NM_000478.6(ALPL):c.881A>C (p.Asp294Ala)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13672	NM_000478.6(ALPL):c.1001G>A (p.Gly334Asp)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13675	NM_000478.6(ALPL):c.407G>A (p.Arg136His)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13683	NM_000478.6(ALPL):c.526G>A (p.Ala176Thr)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457572	NM_000478.6(ALPL):c.980T>G (p.Phe327Cys)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
381585	NM_000478.6(ALPL):c.227A>G (p.Gln76Arg)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299300	NM_006129.5(BMP1):c.584dup (p.Gln197fs)	BMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2735141	NM_001199.4(BMP1):c.2188dup (p.Gln730fs)	BMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3639674	NM_006129.5(BMP1):c.33_44del (p.Gly12_Leu15del)	BMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
37307	NM_006129.5(BMP1):c.34G>C (p.Gly12Arg)	BMP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322111	NM_000088.4(COL1A1):c.1155+1G>C	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328469	NM_000088.4(COL1A1):c.3014T>A (p.Leu1005Ter)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1339426	NM_000088.4(COL1A1):c.4189G>T (p.Glu1397Ter)	COL1A1	Pathogenic	criteria provided, single submitter
1341496	NM_000088.4(COL1A1):c.2831delG	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1380100	NM_000088.4(COL1A1):c.3009del (p.Gly1004fs)	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
1676228	NM_000088.4(COL1A1):c.835_836delinsTCCTGCTGGTCC (p.Asp279fs)	COL1A1	Pathogenic	criteria provided, single submitter
1701980	NM_000088.4(COL1A1):c.543+1G>C	COL1A1	Pathogenic	criteria provided, single submitter
1701982	NM_000088.4(COL1A1):c.580G>C (p.Gly194Arg)	COL1A1	Pathogenic	criteria provided, single submitter
1701983	NM_000088.3(COL1A1):c.700delG	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702090	NM_000088.4(COL1A1):c.1057-2A>T	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702091	NM_000088.4(COL1A1):c.1102G>T (p.Gly368Cys)	COL1A1	Pathogenic	criteria provided, single submitter
1702095	NM_000088.4(COL1A1):c.1614+1G>T	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702098	NM_000088.4(COL1A1):c.1984-2A>C	COL1A1	Pathogenic	criteria provided, single submitter
1702103	NM_000088.4(COL1A1):c.2397dup (p.Gly800fs)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702106	NM_000088.4(COL1A1):c.2560-1G>A	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17312	NM_000088.4(COL1A1):c.994G>A (p.Gly332Arg)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17316	NM_000088.4(COL1A1):c.787G>A (p.Gly263Arg)	COL1A1	Pathogenic	criteria provided, single submitter
17337	NM_000088.4(COL1A1):c.3421C>T (p.Arg1141Ter)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 62 · Orphanet: 79 · 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
COL1A2	Definitive	Autosomal dominant	osteogenesis imperfecta	21
FKBP10	Strong	Autosomal recessive	osteogenesis imperfecta type 11	11
KDELR2	Strong	Autosomal recessive	osteogenesis imperfecta, type 21	4
KIF5B	Strong	Autosomal dominant	osteogenesis imperfecta	2
MBTPS2	Strong	X-linked	osteogenesis imperfecta, type 19	16
TENT5A	Strong	Autosomal recessive	osteogenesis imperfecta, type 18	3
SUCO	Moderate	Autosomal recessive	osteogenesis imperfecta	2
CCDC134	Limited	Autosomal recessive	osteogenesis imperfecta	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MBTPS2	Orphanet:216796	Osteogenesis imperfecta type 1
MBTPS2	Orphanet:216812	Osteogenesis imperfecta type 3
MBTPS2	Orphanet:216820	Osteogenesis imperfecta type 4
MBTPS2	Orphanet:2273	Ichthyosis follicularis-alopecia-photophobia syndrome
MBTPS2	Orphanet:2340	Keratosis follicularis spinulosa decalvans
MBTPS2	Orphanet:659	Mutilating palmoplantar keratoderma with periorificial keratotic plaques
MBTPS2	Orphanet:85284	BRESEK syndrome
FKBP10	Orphanet:1149	Kuskokwim syndrome
FKBP10	Orphanet:216812	Osteogenesis imperfecta type 3
FKBP10	Orphanet:216820	Osteogenesis imperfecta type 4
FKBP10	Orphanet:2771	Bruck syndrome
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
TENT5A	Orphanet:216812	Osteogenesis imperfecta type 3
BMP1	Orphanet:216812	Osteogenesis imperfecta type 3
BMP1	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
SERPINH1	Orphanet:216812	Osteogenesis imperfecta type 3
XYLT2	Orphanet:85194	Spondylo-ocular syndrome
IFITM5	Orphanet:216828	Osteogenesis imperfecta type 5
SP7	Orphanet:1513	Craniodiaphyseal dysplasia
SP7	Orphanet:216820	Osteogenesis imperfecta type 4
CREB3L1	Orphanet:216812	Osteogenesis imperfecta type 3
CREB3L1	Orphanet:79105	Myxofibrosarcoma
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
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

Cohort genes → proteins

30 cohort genes, 29 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	30

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MBTPS2	HGNC:15455	ENSG00000012174	O43462	Membrane-bound transcription factor site-2 protease	gencc,clinvar
FKBP10	HGNC:18169	ENSG00000141756	Q96AY3	Peptidyl-prolyl cis-trans isomerase FKBP10	gencc,clinvar
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	gencc,clinvar
SUCO	HGNC:1240	ENSG00000094975	Q9UBS9	SUN domain-containing ossification factor	gencc
TENT5A	HGNC:18345	ENSG00000112773	Q96IP4	Terminal nucleotidyltransferase 5A	gencc
CCDC134	HGNC:26185	ENSG00000100147	Q9H6E4	Coiled-coil domain-containing protein 134	gencc
KDELR2	HGNC:6305	ENSG00000136240	P33947	ER lumen protein-retaining receptor 2	gencc
KIF5B	HGNC:6324	ENSG00000170759	P33176	Kinesin-1 heavy chain	gencc
BMP1	HGNC:1067	ENSG00000168487	P13497	Bone morphogenetic protein 1	clinvar
SPARC	HGNC:11219	ENSG00000113140	P09486	SPARC	clinvar
WNT1	HGNC:12774	ENSG00000125084	P04628	Proto-oncogene Wnt-1	clinvar
SERPINH1	HGNC:1546	ENSG00000149257	P50454	Serpin H1	clinvar
XYLT2	HGNC:15517	ENSG00000015532	Q9H1B5	Xylosyltransferase 2	clinvar
SNX22	HGNC:16315	ENSG00000157734	Q96L94	Sorting nexin-22	clinvar
IFITM5	HGNC:16644	ENSG00000206013	A6NNB3	Interferon-induced transmembrane protein 5	clinvar
SP7	HGNC:17321	ENSG00000170374	Q8TDD2	Transcription factor Sp7	clinvar
CREB3L1	HGNC:18856	ENSG00000157613	Q96BA8	Cyclic AMP-responsive element-binding protein 3-like protein 1	clinvar
P3H1	HGNC:19316	ENSG00000117385	Q32P28	Prolyl 3-hydroxylase 1	clinvar
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	clinvar
CRTAP	HGNC:2379	ENSG00000170275	O75718	Cartilage-associated protein	clinvar
TMEM38B	HGNC:25535	ENSG00000095209	Q9NVV0	Trimeric intracellular cation channel type B	clinvar
EIF2B2	HGNC:3258	ENSG00000119718	P49770	Translation initiation factor eIF2B subunit beta	clinvar
MFF-DT	HGNC:41067	ENSG00000236432		MFF divergent transcript	clinvar
ALPL	HGNC:438	ENSG00000162551	P05186	Alkaline phosphatase, tissue-nonspecific isozyme	clinvar
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	clinvar
P4HB	HGNC:8548	ENSG00000185624	P07237	Protein disulfide-isomerase	clinvar
SERPINF1	HGNC:8824	ENSG00000132386	P36955	Pigment epithelium-derived factor	clinvar
PLOD2	HGNC:9082	ENSG00000152952	O00469	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	clinvar
PLS3	HGNC:9091	ENSG00000102024	P13797	Plastin-3	clinvar
PPIB	HGNC:9255	ENSG00000166794	P23284	Peptidyl-prolyl cis-trans isomerase B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MBTPS2	Membrane-bound transcription factor site-2 protease	Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2.
FKBP10	Peptidyl-prolyl cis-trans isomerase FKBP10	PPIases accelerate the folding of proteins during protein synthesis.
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
SUCO	SUN domain-containing ossification factor	Required for bone modeling during late embryogenesis.
TENT5A	Terminal nucleotidyltransferase 5A	Cytoplasmic non-canonical poly(A) RNA polymerase that catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3’-OH terminal group and participates in the cytoplasmic polyadenylation.
CCDC134	Coiled-coil domain-containing protein 134	Molecular adapter required to prevent protein hyperglycosylation of HSP90B1: during translation, associates with nascent HSP90B1 and the STT3A catalytic component of the OST-A complex and tethers them to a specialized translocon that forms…
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…
KIF5B	Kinesin-1 heavy chain	Microtubule-dependent motor required for normal distribution of mitochondria and lysosomes.
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.
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.
SERPINH1	Serpin H1	Binds specifically to collagen.
XYLT2	Xylosyltransferase 2	Catalyzes the first step in the biosynthesis of chondroitin sulfate, heparan sulfate and dermatan sulfate proteoglycans, such as DCN.
SNX22	Sorting nexin-22	May be involved in several stages of intracellular trafficking.
IFITM5	Interferon-induced transmembrane protein 5	Required for normal bone mineralization.
SP7	Transcription factor Sp7	Transcriptional activator essential for osteoblast differentiation.
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…
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).
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.
EIF2B2	Translation initiation factor eIF2B subunit beta	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
ALPL	Alkaline phosphatase, tissue-nonspecific isozyme	Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis.
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.
P4HB	Protein disulfide-isomerase	This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds.
SERPINF1	Pigment epithelium-derived factor	Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells.
PLOD2	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens.
PLS3	Plastin-3	Actin-bundling protein.
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: 10 · Difficult: 1 · Unknown: 19 · Druggable fraction: 0.33

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
Enzyme (other)	7	2.8×	0.051
Phosphatase	1	2.8×	0.378
Protease	2	2.4×	0.378
Other/Unknown	19	1.1×	0.378
Transcription factor	1	0.3×	0.979

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBTPS2	Protease	yes	3.4.24.85	MBTPS2, Peptidase_M50, PDZ_sf
FKBP10	Other/Unknown	no		PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily
SUCO	Other/Unknown	no		Galactose-bd-like_sf, SUN_dom, Suco/Slp1-like
TENT5A	Enzyme (other)	yes	2.7.7.19	TET5
CCDC134	Other/Unknown	no		CC134
KDELR2	Other/Unknown	no		ER_ret_rcpt
KIF5B	Enzyme (other)	yes	5.6.1.3	Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
BMP1	Protease	yes	2.7.11.4	EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
SPARC	Other/Unknown	no		Osteonectin_CS, Kazal_dom, Fol_N
WNT1	Other/Unknown	no		Wnt, Wnt1, Wnt_CS
SERPINH1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
XYLT2	Enzyme (other)	yes	2.4.2.26	Glyco_trans_14, XylT_C, XYLT
SNX22	Other/Unknown	no		PX_dom, PX_dom_sf, Sorting_nexin_PX-domain
IFITM5	Other/Unknown	no		CD225/Dispanin_fam, IFITM_antiviral_protein
SP7	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
CREB3L1	Other/Unknown	no		bZIP, bZIP_sf
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
CRTAP	Other/Unknown	no		TPR-like_helical_dom_sf, Collagen_mod_leprecan, Leprecan_dom
TMEM38B	Other/Unknown	no		TRIC_channel
EIF2B2	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
MFF-DT	Other/Unknown	no
ALPL	Phosphatase	yes	3.1.3.1	Alkaline_phosphatase, Alkaline_phosphatase_core_sf, Alkaline_phosphatase_AS
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt
P4HB	Enzyme (other)	yes	5.3.4.1	PDI_thioredoxin-like_dom, Prot_disulphide_isomerase, Thioredoxin_domain
SERPINF1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
PLOD2	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
PLS3	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, EF_hand_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.

26 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)	30
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	12
tibia	6
periodontal ligament	3
jejunal mucosa	3
ascending aorta	2
skin of hip	2
corpus epididymis	2
parotid gland	2
pericardium	2
right adrenal gland	2
caput epididymis	2
right adrenal gland cortex	2
granulocyte	2
left lobe of thyroid gland	2
right lobe of thyroid gland	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
endocervix	2
calcaneal tendon	2
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBTPS2	264	ubiquitous	marker	endothelial cell, tibia, parietal pleura
FKBP10	179	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip
SUCO	297	ubiquitous	marker	corpus epididymis, seminal vesicle, jejunal mucosa
TENT5A	270	ubiquitous	marker	parotid gland, tibia, pericardium
CCDC134	201	ubiquitous	yes	adrenal tissue, right adrenal gland, adrenal gland
KDELR2	301	ubiquitous	marker	stromal cell of endometrium, tibia, mucosa of sigmoid colon
KIF5B	303	ubiquitous	marker	cauda epididymis, caput epididymis, cranial nerve II
BMP1	236	ubiquitous	marker	stromal cell of endometrium, left uterine tube, right adrenal gland cortex
SPARC	306	ubiquitous	marker	tibia, stromal cell of endometrium, periodontal ligament
WNT1	73	tissue_specific	yes	granulocyte, nucleus accumbens, superior frontal gyrus
SERPINH1	265	ubiquitous	marker	stromal cell of endometrium, endometrium epithelium, smooth muscle tissue
XYLT2	237	ubiquitous	marker	body of stomach, stomach, fundus of stomach
SNX22	201	broad	marker	right lobe of thyroid gland, pancreatic ductal cell, left lobe of thyroid gland
IFITM5	83	tissue_specific	marker	body of pancreas, granulocyte, blood
SP7	46	tissue_specific	yes	primordial germ cell in gonad, tibia, male germ line stem cell (sensu Vertebrata) in testis
CREB3L1	231	ubiquitous	marker	nasal cavity epithelium, stromal cell of endometrium, ileal mucosa
P3H1	237	ubiquitous	marker	stromal cell of endometrium, adenohypophysis, tibial nerve
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
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
EIF2B2	298	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
MFF-DT	158		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, bone marrow cell
ALPL	200	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta
P4HB	293	ubiquitous	marker	stromal cell of endometrium, parotid gland, jejunal mucosa
SERPINF1	280	ubiquitous	marker	pigmented layer of retina, pericardium, endocervix
PLOD2	288	ubiquitous	marker	tibia, calcaneal tendon, jejunal mucosa
PLS3	297	ubiquitous	marker	blood vessel layer, calcaneal tendon, visceral pleura
PPIB	295	ubiquitous	marker	stromal cell of endometrium, corpus epididymis, caput epididymis

Protein interactions among cohort

Intra-cohort edges: 72.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
P4HB	5,111
PPIB	4,718
KIF5B	3,606
FKBP10	3,473
SPARC	3,105
EIF2B2	2,800
LRP5	2,619
WNT1	2,506
SP7	2,310

Intra-cohort edges

A	B	Sources
ALPL	COL1A1	string_interaction
ALPL	SP7	string_interaction
BMP1	CRTAP	string_interaction
BMP1	FKBP10	string_interaction
BMP1	IFITM5	string_interaction
BMP1	TMEM38B	string_interaction
CCDC134	IFITM5	string_interaction
CCDC134	TENT5A	string_interaction
CCDC134	TMEM38B	string_interaction
COL1A1	COL1A2	intact
COL1A1	CRTAP	intact, string_interaction
COL1A1	FKBP10	intact
COL1A1	IFITM5	string_interaction
COL1A1	P3H1	intact, string_interaction
COL1A1	PLOD2	intact
COL1A1	PPIB	intact, string_interaction
COL1A1	SP7	string_interaction
COL1A1	SPARC	intact
CREB3L1	CRTAP	string_interaction
CREB3L1	FKBP10	string_interaction
CREB3L1	IFITM5	string_interaction
CREB3L1	MBTPS2	string_interaction
CREB3L1	P3H1	string_interaction
CREB3L1	PLOD2	string_interaction
CREB3L1	PPIB	string_interaction
CREB3L1	SERPINF1	string_interaction
CREB3L1	TMEM38B	string_interaction
CRTAP	FKBP10	string_interaction
CRTAP	IFITM5	string_interaction
CRTAP	MBTPS2	string_interaction
CRTAP	P3H1	biogrid_interaction, intact, string_interaction
CRTAP	PLOD2	string_interaction
CRTAP	PLS3	string_interaction
CRTAP	PPIB	string_interaction
CRTAP	SERPINF1	string_interaction
CRTAP	TENT5A	string_interaction
CRTAP	TMEM38B	string_interaction
FKBP10	IFITM5	string_interaction
FKBP10	MBTPS2	string_interaction
FKBP10	P3H1	string_interaction
FKBP10	PLOD2	string_interaction
FKBP10	PLS3	string_interaction
FKBP10	PPIB	string_interaction
FKBP10	SERPINF1	string_interaction
FKBP10	TENT5A	string_interaction
FKBP10	TMEM38B	string_interaction
IFITM5	MBTPS2	string_interaction
IFITM5	P3H1	string_interaction
IFITM5	PLOD2	string_interaction
IFITM5	PLS3	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF5B	P33176	31
EIF2B2	P49770	27
COL1A1	P02452	14
P4HB	P07237	14
BMP1	P13497	8
PPIB	P23284	8
P3H1	Q32P28	6
CRTAP	O75718	6
PLS3	P13797	6
COL1A2	P08123	5
ALPL	P05186	5
SPARC	P09486	4
SERPINF1	P36955	3
TENT5A	Q96IP4	2
CCDC134	Q9H6E4	2
SNX22	Q96L94	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KDELR2	P33947	93.12
PLOD2	O00469	92.63
SERPINH1	P50454	91.71
FKBP10	Q96AY3	89.19
MBTPS2	O43462	87.78
WNT1	P04628	86.53
XYLT2	Q9H1B5	84.79
TMEM38B	Q9NVV0	80.17
LRP5	O75197	78.65
IFITM5	A6NNB3	65.49
CREB3L1	Q96BA8	55.66
SUCO	Q9UBS9	53.03
SP7	Q8TDD2	52.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 113. Enrichment computed across 30 evidence-associated genes (20 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 20 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	76.7×	9e-14	COL1A2, BMP1, SERPINH1, P3H1, COL1A1, CRTAP, P4HB, PLOD2 (+1 more)
Anchoring fibril formation	3	114.2×	1e-04	COL1A2, BMP1, COL1A1
Crosslinking of collagen fibrils	3	85.7×	2e-04	COL1A2, BMP1, COL1A1
Defective VWF binding to collagen type I	2	380.7×	2e-04	COL1A2, COL1A1
Enhanced cleavage of VWF variant by ADAMTS13	2	285.5×	3e-04	COL1A2, COL1A1
Defective VWF cleavage by ADAMTS13 variant	2	285.5×	3e-04	COL1A2, COL1A1
Enhanced binding of GP1BA variant to VWF multimer:collagen	2	163.1×	9e-04	COL1A2, COL1A1
Defective binding of VWF variant to GPIb:IX:V	2	163.1×	9e-04	COL1A2, COL1A1
CREB3 factors activate genes	2	126.9×	0.001	MBTPS2, CREB3L1
Assembly of collagen fibrils and other multimeric structures	3	30.1×	0.001	COL1A2, BMP1, COL1A1
GP1b-IX-V activation signalling	2	95.2×	0.002	COL1A2, COL1A1
ECM proteoglycans	3	22.5×	0.003	COL1A2, SPARC, COL1A1
Platelet Adhesion to exposed collagen	2	67.2×	0.003	COL1A2, COL1A1
Scavenging by Class A Receptors	2	60.1×	0.004	COL1A2, COL1A1
Fibronectin matrix formation	2	57.1×	0.004	COL1A2, COL1A1
Collagen formation	2	45.7×	0.005	BMP1, SERPINH1
Insulin processing	2	45.7×	0.005	KIF5B, P4HB
RUNX2 regulates osteoblast differentiation	2	45.7×	0.005	SP7, COL1A1
Platelet Aggregation (Plug Formation)	2	43.9×	0.005	COL1A2, COL1A1
Syndecan interactions	2	42.3×	0.006	COL1A2, COL1A1
MET activates PTK2 signaling	2	38.1×	0.007	COL1A2, COL1A1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	2	35.7×	0.007	WNT1, LRP5
GPVI-mediated activation cascade	2	30.9×	0.009	COL1A2, COL1A1
Collagen chain trimerization	2	25.9×	0.012	COL1A2, COL1A1
Developmental Lineage of Pancreatic Ductal Cells	2	22.8×	0.015	COL1A2, COL1A1
Extracellular matrix organization	3	9.5×	0.016	BMP1, SPARC, SERPINH1
Collagen degradation	2	17.6×	0.024	COL1A2, COL1A1
Scavenging by Class H Receptors	1	142.8×	0.027	SPARC
ATF6B (ATF6-beta) activates chaperones	1	142.8×	0.027	MBTPS2
Non-integrin membrane-ECM interactions	2	15.4×	0.027	COL1A2, COL1A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 29 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	8	62.0×	1e-10	FKBP10, COL1A2, BMP1, SERPINH1, P3H1, COL1A1, CRTAP, PLOD2
bone development	5	47.6×	9e-06	WNT1, P3H1, TMEM38B, PLS3, PPIB
regulation of ossification	3	124.5×	2e-04	TENT5A, P3H1, CCDC134
extracellular matrix constituent secretion	2	581.1×	2e-04	CREB3L1, TMEM38B
collagen biosynthetic process	3	109.0×	2e-04	SERPINH1, COL1A1, PLOD2
bone mineralization	4	37.5×	2e-04	COL1A2, IFITM5, TMEM38B, ALPL
protein folding	5	17.8×	3e-04	FKBP10, P3H1, CRTAP, P4HB, PPIB
negative regulation of post-translational protein modification	2	290.6×	6e-04	P3H1, CRTAP
cementum mineralization	2	166.0×	0.002	SP7, ALPL
skeletal system development	4	17.4×	0.002	COL1A2, BMP1, COL1A1, ALPL
osteoblast differentiation	4	16.7×	0.002	SP7, CREB3L1, COL1A1, ALPL
skin morphogenesis	2	96.8×	0.005	COL1A2, COL1A1
response to insulin	3	23.9×	0.006	SP7, COL1A1, ALPL
positive regulation of osteoblast differentiation	3	23.2×	0.006	SUCO, TENT5A, LRP5
negative regulation of cell-substrate adhesion	2	72.6×	0.006	WNT1, COL1A1
collagen metabolic process	2	72.6×	0.006	COL1A2, P3H1
extracellular matrix assembly	2	64.6×	0.008	FKBP10, COL1A2
response to endoplasmic reticulum stress	3	17.3×	0.011	MBTPS2, CREB3L1, P4HB
positive regulation of collagen biosynthetic process	2	44.7×	0.014	SUCO, CREB3L1
bone morphogenesis	2	41.5×	0.016	IFITM5, LRP5
endochondral ossification	2	37.5×	0.019	COL1A1, ALPL
cerebellum formation	1	581.1×	0.019	WNT1
midbrain-hindbrain boundary maturation during brain development	1	581.1×	0.019	WNT1
positive regulation of MyD88-dependent toll-like receptor signaling pathway	1	581.1×	0.019	CCDC134
pyridoxal 5’-phosphate metabolic process	1	581.1×	0.019	ALPL
protein heterotrimerization	1	581.1×	0.019	COL1A2
cellular response to vitamin E	1	581.1×	0.019	COL1A1
mitotic G2 DNA damage checkpoint signaling	2	30.6×	0.021	MBTPS2, CREB3L1
chondrocyte development involved in endochondral bone morphogenesis	1	290.6×	0.025	SERPINH1
peptidyl-proline hydroxylation to 4-hydroxy-L-proline	1	290.6×	0.025	P4HB

Therapeutics

Drugs indicated for this disease

0 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Denosumab	Phase 3 (in late-stage trials)
Medronic Acid	Phase 3 (in late-stage trials)
Romosozumab	Phase 3 (in late-stage trials)
Setrusumab	Phase 3 (in late-stage trials)
Somatropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Calcium, Ergocalciferol, Teriparatide.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 5 · Undrugged: 25

Druggability breadth: 14 of 30 evidence-associated genes (47%) 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
KIF5B	LENVATINIB
ALPL	SULCONAZOLE NITRATE
PPIB	CYCLOSPORINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALPL	7	4
PPIB	4	4
KIF5B	3	4
WNT1	1	1
P4HB	1	2
MBTPS2	0	0
FKBP10	0	0
COL1A2	0	0
SUCO	0	0
TENT5A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LENVATINIB	4	KIF5B
CABOZANTINIB	4	KIF5B
VANDETANIB	4	KIF5B
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
CYCLOSPORINE	4	PPIB
ALISPORIVIR	3	PPIB
ISOQUERCETIN	2	ALPL, P4HB
(-)-EPICATECHIN	2	ALPL
SCY 635	2	PPIB
NIM811	2	PPIB
CIRTUVIVINT	1	WNT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
P4HB	69	Binding:64, Functional:5
ALPL	58	Binding:50, Functional:4, ADMET:3, Toxicity:1
KIF5B	43	Binding:37, Functional:6
BMP1	30	Binding:29, ADMET:1
PPIB	13	Binding:13
WNT1	10	Binding:10
COL1A1	8	Binding:8
COL1A2	4	Functional:4
PLOD2	2	Binding:2
KDELR2	1	Binding:1
SERPINH1	1	Binding:1
EIF2B2	1	Binding:1
LRP5	1	Binding:1
SERPINF1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MBTPS2	3.4.24.85	S2P endopeptidase
TENT5A	2.7.7.19	polynucleotide adenylyltransferase
KIF5B	5.6.1.3	plus-end-directed kinesin ATPase
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
XYLT2	2.4.2.26	protein xylosyltransferase
P3H1	1.14.11.28, 1.14.11.7	proline 3-hydroxylase, procollagen-proline 3-dioxygenase
ALPL	3.1.3.1	alkaline phosphatase
P4HB	5.3.4.1	protein disulfide-isomerase
PLOD2	1.14.11.4, 2.4.1.50	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase
PPIB	5.2.1.8	peptidylprolyl isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 29; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

15 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)
LENVATINIB	4	KIF5B
CABOZANTINIB	4	KIF5B
VANDETANIB	4	KIF5B
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
CYCLOSPORINE	4	PPIB
ALISPORIVIR	3	PPIB
ISOQUERCETIN	2	ALPL, P4HB
(-)-EPICATECHIN	2	ALPL
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)	3	KIF5B, ALPL, PPIB
B	Phased (≥1) drug, not yet approved	2	WNT1, P4HB
C	Druggable family + PDB, no drug	3	TENT5A, BMP1, P3H1
D	Druggable family + AlphaFold only, no drug	3	MBTPS2, XYLT2, PLOD2
E	Difficult family or no structure, no drug	19	FKBP10, COL1A2, SUCO, CCDC134, KDELR2, SPARC, SERPINH1, SNX22, IFITM5, SP7 (+9 more)

Undrugged target profiles

25 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
MBTPS2	0	—
FKBP10	0	—
COL1A2	4	—
SUCO	0	—
TENT5A	0	—
CCDC134	0	—
KDELR2	1	—
BMP1	30	—
SPARC	0	—
SERPINH1	1	—
XYLT2	0	—
SNX22	0	—
IFITM5	0	—
SP7	0	—
CREB3L1	0	—
COL1A1	8	—
TMEM38B	0	—
EIF2B2	1	—
MFF-DT	0	—
LRP5	1	—
SERPINF1	1	—
PLOD2	2	—
PLS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 77.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	41
PHASE3	10
PHASE2	10
PHASE4	6
PHASE1	6
PHASE1/PHASE2	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT05125809	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Placebo for Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT03706482	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Boost Brittle Bones Before Birth
NCT05559801	PHASE1/PHASE2	NOT_YET_RECRUITING	Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT04623606	PHASE1/PHASE2	UNKNOWN	Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	PHASE1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	PHASE1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)
NCT06086613	PHASE1	COMPLETED	A First-in-Human Study Evaluating AGA2115 in Adult Healthy Volunteers
NCT02432625	Not specified	RECRUITING	BBD Longitudinal Study of Osteogenesis Imperfecta
NCT02531087	Not specified	ACTIVE_NOT_RECRUITING	Urinary Biomarkers of OI Pathobiology
NCT02934451	Not specified	ACTIVE_NOT_RECRUITING	Dental Malocclusion and Craniofacial Development in OI
NCT04115774	Not specified	RECRUITING	Registry of Osteogenesis Imperfecta

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALENDRONIC ACID	4	6
RISEDRONIC ACID	4	4
PAMIDRONIC ACID	4	3
ZOLEDRONIC ACID ANHYDROUS	4	3
DENOSUMAB	4	2
ROMOSOZUMAB	4	2
TERIPARATIDE	4	2
CALCIUM	4	1
CALCIUM CARBONATE	4	1
SOMATROPIN	4	1
SETRUSUMAB	3	6
MEDRONIC ACID	3	2
FRESOLIMUMAB	2	1
SAR-439459	1	1
CHEMBL5072826	0	1