Spondyloperipheral dysplasia

Summary

Spondyloperipheral dysplasia (MONDO:0010078) is a disease caused by COL2A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL2A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 85
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0001384	Abnormality of the hip joint	Frequent (30-79%)
HP:0003022	Hypoplasia of the ulna	Frequent (30-79%)
HP:0003071	Flattened epiphysis	Frequent (30-79%)
HP:0003498	Disproportionate short stature	Frequent (30-79%)
HP:0005106	Abnormality of the vertebral endplates	Frequent (30-79%)
HP:0005863	Type E brachydactyly	Frequent (30-79%)
HP:0008788	Delayed pubic bone ossification	Frequent (30-79%)
HP:0010582	Irregular epiphyses	Frequent (30-79%)
HP:0045060	Aplasia/hypoplasia involving bones of the extremities	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0001377	Limited elbow extension	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0003300	Ovoid vertebral bodies	Occasional (5-29%)
HP:0003365	Arthralgia of the hip	Occasional (5-29%)
HP:0008812	Flattened femoral head	Occasional (5-29%)
HP:0010055	Broad hallux	Occasional (5-29%)
HP:0010743	Short metatarsal	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloperipheral dysplasia
Mondo ID	MONDO:0010078
MeSH	C535799
OMIM	271700
Orphanet	1856
DOID	DOID:0112195
NCIT	C135088
SNOMED CT	702339001
UMLS	C0796173
MedGen	163223
GARD	0004994
Is cancer (heuristic)	no

Also known as: spondyloperipheral dysplasia · spondyloperipheral dysplasia-short ulna syndrome

Data availability: 85 ClinVar variants · 2 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › type 2 collagenopathy › spondyloperipheral dysplasia

Related subtypes (13): Stickler syndrome type 1, multiple epiphyseal dysplasia, Beighton type, platyspondylic dysplasia, Torrance type, Kniest dysplasia, spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, achondrogenesis type II, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepiphyseal dysplasia, Stanescu type, hypochondrogenesis, dysplasia of the proximal femoral epiphyses

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

85 retrieved; paginated sample, class counts are floors:

21 likely pathogenic, 18 conflicting classifications of pathogenicity, 13 uncertain significance, 12 pathogenic, 9 benign/likely benign, 7 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074468	NM_001844.5(COL2A1):c.1A>G (p.Met1Val)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1224342	NM_001844.5(COL2A1):c.3121G>A (p.Gly1041Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1299501	NM_001844.5(COL2A1):c.1023+2T>A	COL2A1	Pathogenic	criteria provided, single submitter
1326888	NM_001844.5(COL2A1):c.817-1G>A	COL2A1	Pathogenic	criteria provided, single submitter
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1708151	NM_001844.5(COL2A1):c.3463G>A (p.Gly1155Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17366	NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17380	NM_001844.5(COL2A1):c.4287_4291dup (p.Tyr1431fs)	COL2A1	Pathogenic	no assertion criteria provided
17383	NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17392	NM_001844.5(COL2A1):c.4314C>A (p.Cys1438Ter)	COL2A1	Pathogenic	no assertion criteria provided
17393	NM_001844.5(COL2A1):c.3508G>A (p.Gly1170Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17395	NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195148	NM_001844.5(COL2A1):c.258C>A (p.Cys86Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195742	NM_001844.5(COL2A1):c.1510G>A (p.Gly504Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2859637	NM_001844.5(COL2A1):c.3085G>T (p.Gly1029Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286275	NM_001844.5(COL2A1):c.3311G>A (p.Gly1104Glu)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382798	NM_001844.5(COL2A1):c.3040G>A (p.Gly1014Arg)	COL2A1	Pathogenic	criteria provided, single submitter
449001	NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988569	NM_001844.5(COL2A1):c.2059G>A (p.Gly687Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065456	NM_001844.5(COL2A1):c.1331G>A (p.Gly444Asp)	COL2A1	Likely pathogenic	criteria provided, single submitter
1068151	NM_001844.5(COL2A1):c.2788G>A (p.Gly930Ser)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326894	NM_001844.5(COL2A1):c.1090G>T (p.Gly364Cys)	COL2A1	Likely pathogenic	criteria provided, single submitter
1339718	NM_001844.5(COL2A1):c.3887-2A>G	COL2A1	Likely pathogenic	criteria provided, single submitter
1516689	NM_001844.5(COL2A1):c.1618G>A (p.Gly540Ser)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676793	NM_001844.5(COL2A1):c.1573G>A (p.Gly525Ser)	COL2A1	Likely pathogenic	criteria provided, single submitter
1708062	NM_001844.5(COL2A1):c.2581G>C (p.Gly861Arg)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17389	NM_001844.5(COL2A1):c.4172A>G (p.Tyr1391Cys)	COL2A1	Likely pathogenic	criteria provided, single submitter
3382056	NM_001844.5(COL2A1):c.2771G>A (p.Gly924Glu)	COL2A1	Likely pathogenic	criteria provided, single submitter
3382294	NM_001844.5(COL2A1):c.3293G>A (p.Gly1098Glu)	COL2A1	Likely pathogenic	criteria provided, single submitter
3382404	NM_001844.5(COL2A1):c.3679_3680insAA (p.Gly1227fs)	COL2A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 18 · 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
COL2A1	Definitive	Autosomal dominant	spondyloepiphyseal dysplasia with metatarsal shortening	46

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita

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
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

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
cartilage tissue	1
corpus epididymis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Fibronectin matrix formation	1	571.0×	0.008	COL2A1
MET activates PTK2 signaling	1	380.7×	0.008	COL2A1
Collagen chain trimerization	1	259.6×	0.008	COL2A1
Signaling by PDGF	1	253.8×	0.008	COL2A1
NCAM1 interactions	1	248.3×	0.008	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.008	COL2A1
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.008	COL2A1
Collagen degradation	1	175.7×	0.008	COL2A1
Collagen biosynthesis and modifying enzymes	1	170.4×	0.008	COL2A1
Non-integrin membrane-ECM interactions	1	154.3×	0.008	COL2A1
ECM proteoglycans	1	150.3×	0.008	COL2A1
Integrin cell surface interactions	1	134.3×	0.008	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.011	COL2A1

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
otic vesicle development	1	2808.7×	0.002	COL2A1
anterior head development	1	2808.7×	0.002	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	2407.4×	0.002	COL2A1
proteoglycan metabolic process	1	1872.4×	0.002	COL2A1
notochord development	1	1685.2×	0.002	COL2A1
limb bud formation	1	1532.0×	0.002	COL2A1
embryonic skeletal joint morphogenesis	1	1532.0×	0.002	COL2A1
cartilage condensation	1	766.0×	0.004	COL2A1
tissue homeostasis	1	561.7×	0.004	COL2A1
cellular response to BMP stimulus	1	561.7×	0.004	COL2A1
endochondral ossification	1	543.6×	0.004	COL2A1
extrinsic apoptotic signaling pathway in absence of ligand	1	468.1×	0.004	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	411.0×	0.004	COL2A1
heart morphogenesis	1	374.5×	0.005	COL2A1
chondrocyte differentiation	1	300.9×	0.005	COL2A1
inner ear morphogenesis	1	300.9×	0.005	COL2A1
cartilage development	1	251.5×	0.005	COL2A1
roof of mouth development	1	247.8×	0.005	COL2A1
collagen fibril organization	1	224.7×	0.006	COL2A1
skeletal system development	1	125.8×	0.010	COL2A1
central nervous system development	1	115.4×	0.010	COL2A1
sensory perception of sound	1	100.9×	0.011	COL2A1
regulation of gene expression	1	83.4×	0.013	COL2A1
visual perception	1	79.5×	0.013	COL2A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COL2A1	2	Binding:2

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

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	1	COL2A1

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)
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.