Osteogenesis imperfecta type 2

Summary

Osteogenesis imperfecta type 2 (MONDO:0008147) is a disease caused by COL1A2 (GenCC Definitive), with 6 cohort genes and 1 clinical trial. The dominant Reactome pathway is Collagen biosynthesis and modifying enzymes (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: COL1A2 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 287
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteogenesis imperfecta type 2
Mondo ID	MONDO:0008147
MeSH	C536042
OMIM	166210
Orphanet	216804
DOID	DOID:0110341
ICD-11	2024049157
NCIT	C99001
SNOMED CT	86470003
UMLS	C0268358
MedGen	75673
GARD	0010142
Is cancer (heuristic)	no

Also known as: lethal osteogenesis imperfecta · OI type 2 · OI2 · osteogenesis imperfecta congenita perinatal lethal form · osteogenesis imperfecta type 2 · osteogenesis imperfecta type II · Perinatally lethal OI · Vrolik type of osteogenesis imperfecta

Data availability: 287 ClinVar variants · 7 GenCC gene-disease records · 9 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 2

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 4, 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

287 retrieved; paginated sample, class counts are floors:

120 pathogenic, 58 likely pathogenic, 40 pathogenic/likely pathogenic, 22 conflicting classifications of pathogenicity, 15 benign/likely benign, 15 benign, 14 uncertain significance, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065492	NM_000088.4(COL1A1):c.4291del (p.Thr1431fs)	COL1A1	Pathogenic	criteria provided, single submitter
1075143	NM_000088.4(COL1A1):c.976G>C (p.Gly326Arg)	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
1184518	NM_000088.4(COL1A1):c.3046-1G>T	COL1A1	Pathogenic	no assertion criteria provided
1211288	NM_000088.4(COL1A1):c.3261+1G>A	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
1332753	NM_000088.4(COL1A1):c.2029-1G>T	COL1A1	Pathogenic	criteria provided, single submitter
1332990	NM_000088.4(COL1A1):c.2398-2A>G	COL1A1	Pathogenic	no assertion criteria provided
1332991	NM_000088.4(COL1A1):c.4238A>G (p.Asp1413Gly)	COL1A1	Pathogenic	no assertion criteria provided
1332992	NM_000088.4(COL1A1):c.3316G>T (p.Gly1106Cys)	COL1A1	Pathogenic	no assertion criteria provided
1342741	NM_000088.4(COL1A1):c.1444G>A (p.Gly482Arg)	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
1687324	NM_000088.4(COL1A1):c.4159G>A (p.Ala1387Thr)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17284	NM_000088.4(COL1A1):c.824G>A (p.Gly275Asp)	COL1A1	Pathogenic	no assertion criteria provided
17287	NM_000088.4(COL1A1):c.1705G>C (p.Gly569Arg)	COL1A1	Pathogenic	no assertion criteria provided
17289	NM_000088.4(COL1A1):c.2210G>A (p.Gly737Asp)	COL1A1	Pathogenic	no assertion criteria provided
17290	NM_000088.4(COL1A1):c.2552G>A (p.Gly851Asp)	COL1A1	Pathogenic	no assertion criteria provided
17291	NM_000088.4(COL1A1):c.2533G>A (p.Gly845Arg)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17292	NM_000088.4(COL1A1):c.2605G>T (p.Gly869Cys)	COL1A1	Pathogenic	criteria provided, single submitter
17293	NM_000088.4(COL1A1):c.2686G>T (p.Gly896Cys)	COL1A1	Pathogenic	no assertion criteria provided
17294	NM_000088.4(COL1A1):c.2776G>T (p.Gly926Cys)	COL1A1	Pathogenic	no assertion criteria provided
17297	NM_000088.4(COL1A1):c.3073G>A (p.Gly1025Arg)	COL1A1	Pathogenic	no assertion criteria provided
17298	NM_000088.4(COL1A1):c.3182G>A (p.Gly1061Asp)	COL1A1	Pathogenic	no assertion criteria provided
17299	NM_000088.4(COL1A1):c.3244G>T (p.Gly1082Cys)	COL1A1	Pathogenic	no assertion criteria provided
17300	NM_000088.4(COL1A1):c.3271G>A (p.Gly1091Ser)	COL1A1	Pathogenic	no assertion criteria provided
17301	NM_000088.4(COL1A1):c.3496G>T (p.Gly1166Cys)	COL1A1	Pathogenic	no assertion criteria provided
17302	NM_000088.4(COL1A1):c.3559G>A (p.Gly1187Ser)	COL1A1	Pathogenic	no assertion criteria provided
17306	COL1A1, 9-BP DEL	COL1A1	Pathogenic	no assertion criteria provided
17308	NM_000088.4(COL1A1):c.3969dup (p.Val1324fs)	COL1A1	Pathogenic	no assertion criteria provided
17310	NM_000088.4(COL1A1):c.2156G>A (p.Gly719Asp)	COL1A1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 61 · Orphanet: 28 · 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
CRTAP	Strong	Autosomal recessive	osteogenesis imperfecta type 7	5
MESD	Strong	Autosomal recessive	osteogenesis imperfecta, type 20	4
PPIB	Strong	Autosomal recessive	osteogenesis imperfecta type 9	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
MESD	Orphanet:216804	Osteogenesis imperfecta type 2
P3H1	Orphanet:216804	Osteogenesis imperfecta type 2
P3H1	Orphanet:216812	Osteogenesis imperfecta type 3
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
PPIB	Orphanet:216804	Osteogenesis imperfecta type 2
PPIB	Orphanet:216812	Osteogenesis imperfecta type 3
PPIB	Orphanet:216820	Osteogenesis imperfecta type 4

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	gencc,clinvar
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	gencc,clinvar
MESD	HGNC:13520	ENSG00000117899	Q14696	LRP chaperone MESD	gencc
P3H1	HGNC:19316	ENSG00000117385	Q32P28	Prolyl 3-hydroxylase 1	gencc
CRTAP	HGNC:2379	ENSG00000170275	O75718	Cartilage-associated protein	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)
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).
MESD	LRP chaperone MESD	Chaperone specifically assisting the folding of beta-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs).
P3H1	Prolyl 3-hydroxylase 1	Basement membrane-associated chondroitin sulfate proteoglycan (CSPG).
CRTAP	Cartilage-associated protein	Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues.
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: 2 · Difficult: 0 · Unknown: 4 · 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)	2	4.0×	0.166
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily
MESD	Other/Unknown	no		MESD
P3H1	Enzyme (other)	yes	1.14.11.28	Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, TPR-like_helical_dom_sf
CRTAP	Other/Unknown	no		TPR-like_helical_dom_sf, Collagen_mod_leprecan, Leprecan_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.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	5
periodontal ligament	2
skin of hip	2
epithelial cell of pancreas	1
kidney epithelium	1
pancreatic ductal cell	1
adenohypophysis	1
tibial nerve	1
endocervix	1
tendon of biceps brachii	1
caput epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
MESD	260	ubiquitous	marker	epithelial cell of pancreas, pancreatic ductal cell, kidney epithelium
P3H1	237	ubiquitous	marker	stromal cell of endometrium, adenohypophysis, tibial nerve
CRTAP	288	ubiquitous	marker	tendon of biceps brachii, stromal cell of endometrium, endocervix
PPIB	295	ubiquitous	marker	stromal cell of endometrium, corpus epididymis, caput epididymis

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
PPIB	4,718
P3H1	1,317
MESD	1,046
CRTAP	951
COL1A2	179

Intra-cohort edges

A	B	Sources
COL1A1	COL1A2	intact
COL1A1	CRTAP	intact, string_interaction
COL1A1	P3H1	intact, string_interaction
COL1A1	PPIB	intact, string_interaction
COL1A2	MESD	intact
CRTAP	MESD	string_interaction
CRTAP	P3H1	biogrid_interaction, intact, string_interaction
CRTAP	PPIB	string_interaction
P3H1	PPIB	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A1	P02452	14
PPIB	P23284	8
P3H1	Q32P28	6
CRTAP	O75718	6
COL1A2	P08123	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MESD	Q14696	67.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 6 evidence-associated genes (5 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 5 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	5	170.4×	2e-10	COL1A1, COL1A2, P3H1, CRTAP, PPIB
Defective VWF binding to collagen type I	2	1522.7×	7e-06	COL1A1, COL1A2
Enhanced cleavage of VWF variant by ADAMTS13	2	1142.0×	7e-06	COL1A1, COL1A2
Defective VWF cleavage by ADAMTS13 variant	2	1142.0×	7e-06	COL1A1, COL1A2
Enhanced binding of GP1BA variant to VWF multimer:collagen	2	652.6×	2e-05	COL1A1, COL1A2
Defective binding of VWF variant to GPIb:IX:V	2	652.6×	2e-05	COL1A1, COL1A2
GP1b-IX-V activation signalling	2	380.7×	4e-05	COL1A1, COL1A2
Anchoring fibril formation	2	304.5×	6e-05	COL1A1, COL1A2
Platelet Adhesion to exposed collagen	2	268.7×	7e-05	COL1A1, COL1A2
Scavenging by Class A Receptors	2	240.4×	7e-05	COL1A1, COL1A2
Fibronectin matrix formation	2	228.4×	7e-05	COL1A1, COL1A2
Crosslinking of collagen fibrils	2	228.4×	7e-05	COL1A1, COL1A2
Platelet Aggregation (Plug Formation)	2	175.7×	1e-04	COL1A1, COL1A2
Syndecan interactions	2	169.2×	1e-04	COL1A1, COL1A2
MET activates PTK2 signaling	2	152.3×	1e-04	COL1A1, COL1A2
GPVI-mediated activation cascade	2	123.5×	2e-04	COL1A1, COL1A2
Collagen chain trimerization	2	103.8×	2e-04	COL1A1, COL1A2
Developmental Lineage of Pancreatic Ductal Cells	2	91.4×	3e-04	COL1A1, COL1A2
Assembly of collagen fibrils and other multimeric structures	2	80.1×	4e-04	COL1A1, COL1A2
Collagen degradation	2	70.3×	5e-04	COL1A1, COL1A2
Non-integrin membrane-ECM interactions	2	61.7×	6e-04	COL1A1, COL1A2
ECM proteoglycans	2	60.1×	6e-04	COL1A1, COL1A2
Integrin cell surface interactions	2	53.7×	7e-04	COL1A1, COL1A2
Cell surface interactions at the vascular wall	2	38.1×	0.001	COL1A1, COL1A2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	34.9×	0.001	COL1A1, COL1A2
RUNX2 regulates osteoblast differentiation	1	91.4×	0.012	COL1A1
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	61.7×	0.017	COL1A2
SARS-CoV-1 activates/modulates innate immune responses	1	54.4×	0.019	PPIB
Interleukin-4 and Interleukin-13 signaling	1	20.6×	0.048	COL1A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	149.8×	4e-07	COL1A1, COL1A2, P3H1, CRTAP
protein folding	4	68.9×	4e-06	MESD, P3H1, CRTAP, PPIB
negative regulation of post-translational protein modification	2	1404.3×	2e-05	P3H1, CRTAP
skin morphogenesis	2	468.1×	1e-04	COL1A1, COL1A2
collagen metabolic process	2	351.1×	2e-04	COL1A2, P3H1
protein stabilization	3	33.4×	8e-04	P3H1, CRTAP, PPIB
blood vessel development	2	124.8×	0.001	COL1A1, COL1A2
cellular response to amino acid stimulus	2	102.1×	0.001	COL1A1, COL1A2
bone development	2	92.1×	0.002	P3H1, PPIB
protein heterotrimerization	1	2808.7×	0.002	COL1A2
cellular response to vitamin E	1	2808.7×	0.002	COL1A1
cellular response to fluoride	1	1404.3×	0.004	COL1A1
skeletal system development	2	41.9×	0.005	COL1A1, COL1A2
tooth mineralization	1	936.2×	0.005	COL1A1
protein hydroxylation	1	561.7×	0.008	P3H1
cellular response to acetaldehyde	1	561.7×	0.008	COL1A1
intramembranous ossification	1	468.1×	0.009	COL1A1
cartilage development involved in endochondral bone morphogenesis	1	401.2×	0.010	COL1A1
bone trabecula formation	1	351.1×	0.011	COL1A1
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	312.1×	0.012	MESD
host-mediated activation of viral genome replication	1	280.9×	0.012	PPIB
regulation of protein secretion	1	255.3×	0.013	P3H1
host-mediated activation of viral process	1	234.1×	0.013	PPIB
collagen-activated tyrosine kinase receptor signaling pathway	1	216.1×	0.014	COL1A1
regulation of ossification	1	200.6×	0.014	P3H1
response to hyperoxia	1	187.2×	0.015	COL1A1
negative regulation of cell-substrate adhesion	1	175.5×	0.015	COL1A1
collagen biosynthetic process	1	175.5×	0.015	COL1A1
extracellular matrix assembly	1	156.0×	0.016	COL1A2
response to steroid hormone	1	140.4×	0.017	COL1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 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
COL1A1	0	0
COL1A2	0	0
MESD	0	0
P3H1	0	0
CRTAP	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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PPIB	13	Binding:13
COL1A1	8	Binding:8
COL1A2	4	Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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

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	0
C	Druggable family + PDB, no drug	1	P3H1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	COL1A1, COL1A2, MESD, CRTAP

Undrugged target profiles

5 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
COL1A1	8	—
COL1A2	4	—
MESD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01061099	PHASE1	COMPLETED	Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta