Osteogenesis imperfecta type 9

Summary

Osteogenesis imperfecta type 9 (MONDO:0009805) is a disease caused by PPIB (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PPIB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteogenesis imperfecta type 9
Mondo ID	MONDO:0009805
MeSH	C564921
OMIM	259440
DOID	DOID:0110349
UMLS	C1850169
MedGen	376720
GARD	0010619
Is cancer (heuristic)	no

Also known as: OI 9 · OI type IX · OI9 · osteogenesis imperfecta caused by mutation in PPIB · osteogenesis imperfecta sillence type II/III without abnormality of type I collagen · osteogenesis imperfecta type 9 · osteogenesis imperfecta, type IX · PPIB osteogenesis imperfecta

Data availability: 49 ClinVar variants · 3 GenCC gene-disease records.

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 9

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, 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

49 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 5 conflicting classifications of pathogenicity, 4 pathogenic, 4 benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344893	NM_000942.5(PPIB):c.434_435del (p.Lys145fs)	PPIB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31843	NM_000942.5(PPIB):c.120del (p.Val42fs)	PPIB	Pathogenic	no assertion criteria provided
31844	NM_000942.5(PPIB):c.313G>A (p.Gly105Arg)	PPIB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16925	NM_000942.5(PPIB):c.556_559del (p.Lys186fs)	SNX22	Pathogenic	criteria provided, multiple submitters, no conflicts
16926	NM_000942.5(PPIB):c.451C>T (p.Gln151Ter)	SNX22	Pathogenic	criteria provided, single submitter
41422	NM_000942.5(PPIB):c.563_566del (p.Asp188fs)	SNX22	Pathogenic	no assertion criteria provided
3577594	NM_000942.5(PPIB):c.269del (p.Asn90fs)	PPIB	Likely pathogenic	criteria provided, single submitter
3577595	NM_000942.5(PPIB):c.25A>G (p.Met9Val)	PPIB	Likely pathogenic	criteria provided, single submitter
3577596	NM_000942.5(PPIB):c.1A>T (p.Met1Leu)	PPIB	Likely pathogenic	criteria provided, single submitter
316701	NM_000942.5(PPIB):c.597C>T (p.Ile199=)	PPIB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886216	NM_000942.5(PPIB):c.528+14G>A	PPIB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887220	NM_000942.5(PPIB):c.249+12G>A	PPIB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888474	NM_000942.5(PPIB):c.-9C>G	PPIB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886217	NM_000942.5(PPIB):c.444C>T (p.Asn148=)	SNX22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343507	NM_000942.5(PPIB):c.224A>G (p.Asn75Ser)	PPIB	Uncertain significance	criteria provided, multiple submitters, no conflicts
16927	NM_000942.5(PPIB):c.26T>G (p.Met9Arg)	PPIB	Uncertain significance	criteria provided, single submitter
316702	NM_000942.5(PPIB):c.426C>T (p.Asn142=)	PPIB	Uncertain significance	criteria provided, single submitter
316704	NM_000942.5(PPIB):c.279C>T (p.Phe93=)	PPIB	Uncertain significance	criteria provided, single submitter
316705	NM_000942.5(PPIB):c.58G>T (p.Gly20Trp)	PPIB	Uncertain significance	criteria provided, single submitter
316706	NM_000942.4(PPIB):c.-56C>A	PPIB	Uncertain significance	criteria provided, single submitter
316707	NM_000942.4(PPIB):c.-57G>A	PPIB	Uncertain significance	criteria provided, single submitter
316708	NM_000942.4(PPIB):c.-91A>C	PPIB	Uncertain significance	criteria provided, multiple submitters, no conflicts
316709	NM_000942.4(PPIB):c.-94C>G	PPIB	Uncertain significance	criteria provided, single submitter
316710	NM_000942.4(PPIB):c.-98C>A	PPIB	Uncertain significance	criteria provided, single submitter
316711	NM_000942.4(PPIB):c.-118A>G	PPIB	Uncertain significance	criteria provided, single submitter
316712	NM_000942.4(PPIB):c.-136C>T	PPIB	Uncertain significance	criteria provided, single submitter
316713	NM_000942.4(PPIB):c.-139C>T	PPIB	Uncertain significance	criteria provided, single submitter
884248	NM_000942.4(PPIB):c.-92C>A	PPIB	Uncertain significance	criteria provided, single submitter
885311	NM_000942.5(PPIB):c.*154C>T	PPIB	Uncertain significance	criteria provided, single submitter
885312	NM_000942.5(PPIB):c.*80C>T	PPIB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
PPIB	Strong	Autosomal recessive	osteogenesis imperfecta type 9	6

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPIB	HGNC:9255	ENSG00000166794	P23284	Peptidyl-prolyl cis-trans isomerase B	gencc,clinvar
SNX22	HGNC:16315	ENSG00000157734	Q96L94	Sorting nexin-22	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SNX22	Sorting nexin-22	May be involved in several stages of intracellular trafficking.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPIB	Enzyme (other)	yes	5.2.1.8	Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-like_dom_sf
SNX22	Other/Unknown	no		PX_dom, PX_dom_sf, Sorting_nexin_PX-domain

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
stromal cell of endometrium	1
left lobe of thyroid gland	1
pancreatic ductal cell	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPIB	295	ubiquitous	marker	stromal cell of endometrium, corpus epididymis, caput epididymis
SNX22	201	broad	marker	right lobe of thyroid gland, pancreatic ductal cell, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPIB	4,718
SNX22	424

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPIB	P23284	8
SNX22	Q96L94	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.006	PPIB
Collagen biosynthesis and modifying enzymes	1	170.4×	0.006	PPIB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
host-mediated activation of viral genome replication	1	842.6×	0.006	PPIB
host-mediated activation of viral process	1	702.2×	0.006	PPIB
positive regulation of multicellular organism growth	1	247.8×	0.011	PPIB
neutrophil chemotaxis	1	142.8×	0.012	PPIB
bone development	1	138.1×	0.012	PPIB
protein folding	1	51.7×	0.026	PPIB
protein stabilization	1	33.4×	0.034	PPIB
protein transport	1	21.9×	0.045	SNX22

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
SNX22	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): 1.

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

Symbol	Assays	Type breakdown
PPIB	13	Binding:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPIB	5.2.1.8	peptidylprolyl isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SNX22

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SNX22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.