Opsismodysplasia

Summary

Opsismodysplasia (MONDO:0009785) is a disease caused by INPPL1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: INPPL1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 55
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001182	Tapered finger	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0003173	Hypoplastic pubic bone	Very frequent (80-99%)
HP:0003175	Hypoplastic ischia	Very frequent (80-99%)
HP:0003177	Squared iliac bones	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0008479	Hypoplastic vertebral bodies	Very frequent (80-99%)
HP:0100569	Abnormally ossified vertebrae	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0005469	Flat occiput	Frequent (30-79%)
HP:0000592	Blue sclerae	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0011304	Broad thumb	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	opsismodysplasia
Mondo ID	MONDO:0009785
MeSH	C537122
OMIM	258480
Orphanet	2746
ICD-11	2147268863
SNOMED CT	254068007
UMLS	C0432219
MedGen	140927
GARD	0004098
Is cancer (heuristic)	no

Also known as: opsismodysplasia · OPSMD

Data availability: 55 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylodysplastic dysplasia › severe spondylodysplastic dysplasia › opsismodysplasia

Related subtypes (4): achondrogenesis type IA, spondylometaphyseal dysplasia, Sedaghatian type, schneckenbecken dysplasia, autosomal recessive spondylometaphyseal dysplasia, Megarbane type

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

55 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 16 pathogenic, 9 likely pathogenic, 3 pathogenic/likely pathogenic, 3 benign, 2 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
235822	NM_001567.3(INPPL1):c.[24_39del16;753G>C]		Pathogenic	no assertion criteria provided
235823	NM_001567.3(INPPL1):c.[1687_1691delACCTC;35dupG]		Pathogenic	no assertion criteria provided
235825	NM_001567.3(INPPL1):c.[2415+1G>A;768_769delAG]		Pathogenic	no assertion criteria provided
431061	NM_001567.3(INPPL1):c.[1115delG];[2331C>G]		Pathogenic	no assertion criteria provided
1027944	NM_001567.4(INPPL1):c.2213-2A>C	INPPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323117	NM_001567.4(INPPL1):c.306C>G (p.Tyr102Ter)	INPPL1	Pathogenic	criteria provided, single submitter
1709919	NM_001567.4(INPPL1):c.3562dup (p.Leu1188fs)	INPPL1	Pathogenic	criteria provided, single submitter
235824	NM_001567.4(INPPL1):c.768_769del (p.Glu258fs)	INPPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235826	NM_001567.4(INPPL1):c.2071C>T (p.Arg691Trp)	INPPL1	Pathogenic	no assertion criteria provided
3362516	NM_001567.4(INPPL1):c.1945C>T (p.Arg649Ter)	INPPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39475	NM_001567.4(INPPL1):c.768del (p.Glu258fs)	INPPL1	Pathogenic	no assertion criteria provided
39476	NM_001567.4(INPPL1):c.2415+1G>A	INPPL1	Pathogenic	no assertion criteria provided
39477	NM_001567.4(INPPL1):c.1975C>T (p.Pro659Ser)	INPPL1	Pathogenic	no assertion criteria provided
39478	NM_001567.4(INPPL1):c.278_282del (p.Gln93fs)	INPPL1	Pathogenic	no assertion criteria provided
39479	NM_001567.4(INPPL1):c.1201C>T (p.Arg401Trp)	INPPL1	Pathogenic	no assertion criteria provided
39480	NM_001567.4(INPPL1):c.2164T>A (p.Phe722Ile)	INPPL1	Pathogenic	no assertion criteria provided
39481	NM_001567.4(INPPL1):c.94_121del (p.Glu32fs)	INPPL1	Pathogenic	criteria provided, multiple submitters, no conflicts
431058	NM_001567.4(INPPL1):c.1845dup (p.Ile616fs)	INPPL1	Pathogenic	no assertion criteria provided
931442	NM_001567.4(INPPL1):c.939+1G>A	INPPL1	Pathogenic	criteria provided, single submitter
1029357	NM_001567.4(INPPL1):c.3549_3550insA (p.Glu1184fs)	INPPL1	Likely pathogenic	criteria provided, single submitter
1324584	NM_001567.4(INPPL1):c.2356C>T (p.Gln786Ter)	INPPL1	Likely pathogenic	criteria provided, single submitter
1339494	NM_001567.4(INPPL1):c.3466del (p.Arg1156fs)	INPPL1	Likely pathogenic	criteria provided, single submitter
1683469	NM_001567.4(INPPL1):c.115_128del (p.Gly39fs)	INPPL1	Likely pathogenic	criteria provided, single submitter
242401	NM_001567.4(INPPL1):c.24_39del (p.Gly9fs)	INPPL1	Likely pathogenic	criteria provided, single submitter
3891391	NM_001567.4(INPPL1):c.1184_1185dup (p.Val396fs)	INPPL1	Likely pathogenic	criteria provided, single submitter
39473	NM_001567.4(INPPL1):c.1976C>T (p.Pro659Leu)	INPPL1	Likely pathogenic	criteria provided, single submitter
39474	NM_001567.4(INPPL1):c.545C>A (p.Ser182Ter)	INPPL1	Likely pathogenic	criteria provided, single submitter
4819360	NM_001567.4(INPPL1):c.1933A>T (p.Lys645Ter)	INPPL1	Likely pathogenic	criteria provided, single submitter
1016626	NM_001567.4(INPPL1):c.3563T>G (p.Leu1188Arg)	INPPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032754	NM_001567.4(INPPL1):c.2326+9C>T	INPPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
INPPL1	Definitive	Autosomal recessive	opsismodysplasia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
INPPL1	Orphanet:2746	Opsismodysplasia
INPPL1	Orphanet:3144	Schneckenbecken dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
INPPL1	HGNC:6080	ENSG00000165458	O15357	Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
INPPL1	Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinas…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
INPPL1	Scaffold/PPI	no	3.1.3.56	IPPc, SH2, SAM

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of stomach	1
right lobe of thyroid gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
INPPL1	223	ubiquitous	marker	mucosa of stomach, stromal cell of endometrium, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INPPL1	2,630

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INPPL1	O15357	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 1 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
Interleukin-2 family signaling	1	634.4×	0.006	INPPL1
Inositol phosphate metabolism	1	475.8×	0.006	INPPL1
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.006	INPPL1
Interleukin receptor SHC signaling	1	407.9×	0.006	INPPL1
PI Metabolism	1	356.9×	0.006	INPPL1
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.006	INPPL1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.006	INPPL1
Synthesis of PIPs at the plasma membrane	1	211.5×	0.008	INPPL1
Phospholipid metabolism	1	200.3×	0.008	INPPL1
Signaling by Interleukins	1	64.2×	0.022	INPPL1
Cytokine Signaling in Immune system	1	40.8×	0.031	INPPL1
Metabolism of lipids	1	31.6×	0.037	INPPL1
Immune System	1	13.0×	0.083	INPPL1
Metabolism	1	11.6×	0.086	INPPL1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of actin filament organization	1	2407.4×	0.005	INPPL1
negative regulation of insulin-like growth factor receptor signaling pathway	1	2106.5×	0.005	INPPL1
ruffle assembly	1	1296.3×	0.006	INPPL1
phosphatidylinositol dephosphorylation	1	648.1×	0.007	INPPL1
endochondral ossification	1	543.6×	0.007	INPPL1
regulation of immune response	1	495.6×	0.007	INPPL1
establishment of mitotic spindle orientation	1	481.5×	0.007	INPPL1
immune system process	1	391.9×	0.007	INPPL1
phosphatidylinositol biosynthetic process	1	366.4×	0.007	INPPL1
ERK1 and ERK2 cascade	1	318.0×	0.007	INPPL1
glucose metabolic process	1	255.3×	0.007	INPPL1
response to insulin	1	230.8×	0.007	INPPL1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	INPPL1
post-embryonic development	1	205.5×	0.007	INPPL1
regulation of protein localization	1	205.5×	0.007	INPPL1
actin filament organization	1	118.7×	0.012	INPPL1
endocytosis	1	95.2×	0.014	INPPL1
gene expression	1	79.9×	0.015	INPPL1
negative regulation of gene expression	1	69.1×	0.017	INPPL1
negative regulation of cell population proliferation	1	42.1×	0.026	INPPL1
cell adhesion	1	37.5×	0.028	INPPL1
apoptotic process	1	28.7×	0.035	INPPL1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
INPPL1	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
INPPL1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	INPPL1
CRIZOTINIB	4	INPPL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
INPPL1	38	Binding:38

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
INPPL1	3.1.3.56, 3.1.3.86	inositol-polyphosphate 5-phosphatase, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
ESTRAMUSTINE PHOSPHATE	4	INPPL1
CRIZOTINIB	4	INPPL1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	INPPL1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.