Pseudoachondroplasia

Summary

Pseudoachondroplasia (MONDO:0008322) is a disease caused by COMP (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include resveratrol.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide)
• Causal gene: COMP (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 130
• Phenotypes (HPO): 45
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.3	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0008873	Disproportionate short-limb short stature	Very frequent (80-99%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002663	Delayed epiphyseal ossification	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0002761	Generalized joint laxity	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0003016	Metaphyseal widening	Frequent (30-79%)
HP:0003025	Metaphyseal irregularity	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0005720	Shortening of all metacarpals	Frequent (30-79%)
HP:0006149	Increased laxity of fingers	Frequent (30-79%)
HP:0009803	Short phalanx of finger	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0010582	Irregular epiphyses	Frequent (30-79%)
HP:0020152	Distal joint laxity	Frequent (30-79%)
HP:0045086	Knee joint hypermobility	Frequent (30-79%)
HP:0100531	Wind-swept deformity of the knees	Frequent (30-79%)
HP:0001377	Limited elbow extension	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0002970	Genu varum	Occasional (5-29%)
HP:0003015	Flared metaphysis	Occasional (5-29%)
HP:0003090	Hypoplasia of the capital femoral epiphysis	Occasional (5-29%)
HP:0003093	Limited hip extension	Occasional (5-29%)
HP:0003180	Flat acetabular roof	Occasional (5-29%)
HP:0003756	Skeletal myopathy	Occasional (5-29%)
HP:0004236	Irregular carpal bones	Occasional (5-29%)
HP:0004568	Beaking of vertebral bodies	Occasional (5-29%)
HP:0006460	Increased laxity of ankles	Occasional (5-29%)
HP:0006499	Abnormality of femoral epiphysis	Occasional (5-29%)
HP:0008807	Acetabular dysplasia	Occasional (5-29%)
HP:0008833	Irregular acetabular roof	Occasional (5-29%)
HP:0008839	Hypoplastic pelvis	Occasional (5-29%)
HP:0009107	Abnormal ossification involving the femoral head and neck	Occasional (5-29%)
HP:0010579	Cone-shaped epiphysis	Occasional (5-29%)
HP:0010585	Small epiphyses	Occasional (5-29%)
HP:0100864	Short femoral neck	Occasional (5-29%)
HP:0003311	Hypoplasia of the odontoid process	Very rare (<1-4%)
HP:0010646	Cervical spine instability	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudoachondroplasia
Mondo ID	MONDO:0008322
MeSH	C535819
OMIM	177170
Orphanet	750
DOID	DOID:0080047
ICD-11	1192649257
NCIT	C118635
SNOMED CT	22567005
UMLS	C0410538
MedGen	98378
GARD	0004540
NORD	1625
Is cancer (heuristic)	no

Also known as: PSACH · pseudoachondroplasia · Pseudoachondroplastic dysplasia · pseudoachondroplastic dysplasia · Pseudoachondroplastic spondyloepiphyseal dysplasia · Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome · spondyloepiphyseal dysplasia, PSEUDOACHONDROPLASTIC

Data availability: 130 ClinVar variants · 4 GenCC gene-disease records · 2 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 › pseudoachondroplasia

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, 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, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

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

130 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 20 conflicting classifications of pathogenicity, 20 likely pathogenic, 15 pathogenic, 14 pathogenic/likely pathogenic, 13 benign/likely benign, 9 benign, 2 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1180714	NM_000095.3(COMP):c.1403G>T (p.Cys468Phe)	COMP	Pathogenic	criteria provided, multiple submitters, no conflicts
1332831	NM_000095.3(COMP):c.925G>A (p.Gly309Arg)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373104	NM_000095.3(COMP):c.895G>A (p.Gly299Arg)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404680	NM_000095.3(COMP):c.1114GAC[2] (p.Asp374del)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404727	NM_000095.3(COMP):c.806A>G (p.Asp269Gly)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679945	NM_000095.3(COMP):c.868G>T (p.Asp290Tyr)	COMP	Pathogenic	no assertion criteria provided
1683450	NM_000095.3(COMP):c.1309G>C (p.Asp437His)	COMP	Pathogenic	criteria provided, single submitter
1723871	NM_000095.3(COMP):c.1045G>C (p.Asp349His)	COMP	Pathogenic	criteria provided, single submitter
40988	NM_000095.3(COMP):c.1405GAC[4] (p.Asp473del)	COMP	Pathogenic	criteria provided, multiple submitters, no conflicts
40994	NM_000095.3(COMP):c.1754C>G (p.Thr585Arg)	COMP	Pathogenic	criteria provided, single submitter
40995	NM_000095.3(COMP):c.1754C>T (p.Thr585Met)	COMP	Pathogenic	criteria provided, multiple submitters, no conflicts
40996	NM_000095.3(COMP):c.1760A>G (p.His587Arg)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40997	NM_000095.3(COMP):c.2155G>A (p.Gly719Ser)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4280638	NM_000095.3(COMP):c.895G>C (p.Gly299Arg)	COMP	Pathogenic	criteria provided, single submitter
4291809	NM_000095.3(COMP):c.1319G>T (p.Gly440Val)	COMP	Pathogenic	criteria provided, single submitter
803547	NM_000095.3(COMP):c.1552G>C (p.Asp518His)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803548	NM_000095.3(COMP):c.1315G>T (p.Asp439Tyr)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807399	NM_000095.3(COMP):c.1368GGA[1] (p.Glu457del)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
818218	NM_000095.3(COMP):c.874T>C (p.Cys292Arg)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9183	NM_000095.3(COMP):c.1414G>T (p.Asp472Tyr)	COMP	Pathogenic	no assertion criteria provided
9185	NM_000095.3(COMP):c.1375_1377del (p.Ser459del)	COMP	Pathogenic	no assertion criteria provided
9188	NM_000095.3(COMP):c.982T>C (p.Cys328Arg)	COMP	Pathogenic	no assertion criteria provided
9191	NM_000095.3(COMP):c.1418A>G (p.Asp473Gly)	COMP	Pathogenic	no assertion criteria provided
9192	NM_000095.3(COMP):c.1405GAC[7] (p.Asp472_Asp473dup)	COMP	Pathogenic/Likely pathogenic	no assertion criteria provided
9193	NM_000095.3(COMP):c.1405GAC[6] (p.Asp473dup)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9194	NM_000095.3(COMP):c.2156G>A (p.Gly719Asp)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9195	NM_000095.3(COMP):c.1042T>C (p.Cys348Arg)	COMP	Pathogenic	criteria provided, single submitter
9196	NM_000095.3(COMP):c.917_976-68del	COMP	Pathogenic	no assertion criteria provided
988351	NM_000095.3(COMP):c.1153G>A (p.Asp385Asn)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332846	NM_000095.3(COMP):c.983G>T (p.Cys328Phe)	COMP	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
COMP	Definitive	Autosomal dominant	pseudoachondroplasia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COMP	Orphanet:750	Pseudoachondroplasia
COMP	Orphanet:93308	Multiple epiphyseal dysplasia type 1
MATN3	Orphanet:156728	Spondyloepimetaphyseal dysplasia, matrilin-3 type
MATN3	Orphanet:93311	Multiple epiphyseal dysplasia type 5

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
COMP	HGNC:2227	ENSG00000105664	P49747	Cartilage oligomeric matrix protein	gencc,clinvar
MATN3	HGNC:6909	ENSG00000132031	O15232	Matrilin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COMP	Cartilage oligomeric matrix protein	Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin.
MATN3	Matrilin-3	Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COMP	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, Thrombospondin_3-like_rpt
MATN3	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, VWF_A

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	2
tibia	2
calcaneal tendon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COMP	195	broad	marker	tibia, cartilage tissue, calcaneal tendon
MATN3	167	broad	yes	tibia, cartilage tissue, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COMP	2,205
MATN3	1,918

Intra-cohort edges

A	B	Sources
COMP	MATN3	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COMP	P49747	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATN3	O15232	79.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ECM proteoglycans	2	150.3×	3e-04	COMP, MATN3
Integrin cell surface interactions	1	67.2×	0.040	COMP
Post-translational protein phosphorylation	1	50.1×	0.040	MATN3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.040	MATN3
Extracellular matrix organization	1	31.6×	0.044	MATN3
Post-translational protein modification	1	9.6×	0.118	MATN3
Metabolism of proteins	1	6.2×	0.155	MATN3

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
negative regulation of hemostasis	1	8426.0×	0.002	COMP
skeletal system development	2	125.8×	0.002	COMP, MATN3
tendon development	1	2106.5×	0.004	COMP
vascular associated smooth muscle contraction	1	1685.2×	0.004	COMP
cartilage homeostasis	1	1685.2×	0.004	COMP
musculoskeletal movement	1	1404.3×	0.004	COMP
growth plate cartilage development	1	1053.2×	0.004	COMP
positive regulation of chondrocyte proliferation	1	936.2×	0.004	COMP
vascular associated smooth muscle cell development	1	842.6×	0.004	COMP
chondrocyte proliferation	1	526.6×	0.006	COMP
chondrocyte development	1	468.1×	0.006	COMP
regulation of bone mineralization	1	366.4×	0.007	COMP
artery morphogenesis	1	337.0×	0.007	COMP
skin development	1	221.7×	0.010	COMP
limb development	1	205.5×	0.010	COMP
platelet aggregation	1	168.5×	0.011	COMP
response to unfolded protein	1	150.5×	0.012	COMP
cellular senescence	1	147.8×	0.012	COMP
bone mineralization	1	135.9×	0.012	COMP
protein secretion	1	131.7×	0.012	COMP
cartilage development	1	125.8×	0.012	MATN3
collagen fibril organization	1	112.3×	0.013	COMP
BMP signaling pathway	1	100.3×	0.013	COMP
animal organ morphogenesis	1	95.8×	0.013	COMP
protein processing	1	85.1×	0.015	COMP
multicellular organism growth	1	68.5×	0.017	COMP
extracellular matrix organization	1	61.1×	0.018	MATN3
protein homooligomerization	1	61.1×	0.018	COMP
regulation of gene expression	1	41.7×	0.025	COMP
negative regulation of apoptotic process	1	17.4×	0.059	COMP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COMP	0	0
MATN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	COMP, MATN3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COMP	0	—
MATN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03866200	PHASE2	TERMINATED	Resveratrol Trial for Relief of Pain in Pseudoachondroplasia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RESVERATROL	3	1