Kniest dysplasia

Summary

Kniest dysplasia (MONDO:0007987) is a disease caused by COL2A1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: COL2A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 85
• Phenotypes (HPO): 51
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0008271	Abnormal cartilage collagen	Obligate (100%)
HP:0000311	Round face	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0001367	Abnormal joint morphology	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001591	Bell-shaped thorax	Very frequent (80-99%)
HP:0002663	Delayed epiphyseal ossification	Very frequent (80-99%)
HP:0003037	Enlarged joints	Very frequent (80-99%)
HP:0003330	Abnormal bone structure	Very frequent (80-99%)
HP:0003498	Disproportionate short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0007773	Vitreoretinopathy	Very frequent (80-99%)
HP:0007964	Degenerative vitreoretinopathy	Very frequent (80-99%)
HP:0011003	High myopia	Very frequent (80-99%)
HP:0012069	Keratan sulfate excretion in urine	Very frequent (80-99%)
HP:0012785	Flexion contracture of finger	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0000947	Dumbbell-shaped long bone	Frequent (30-79%)
HP:0003016	Metaphyseal widening	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003040	Arthropathy	Frequent (30-79%)
HP:0003051	Enlarged metaphyses	Frequent (30-79%)
HP:0003311	Hypoplasia of the odontoid process	Frequent (30-79%)
HP:0003521	Disproportionate short-trunk short stature	Frequent (30-79%)
HP:0007992	Lattice retinal degeneration	Frequent (30-79%)
HP:0008063	Aplasia/Hypoplasia of the lens	Frequent (30-79%)
HP:0009815	Aplasia/hypoplasia of the extremities	Frequent (30-79%)
HP:0010306	Short thorax	Frequent (30-79%)
HP:0010574	Abnormality of the epiphysis of the femoral head	Frequent (30-79%)
HP:0010580	Enlarged epiphyses	Frequent (30-79%)
HP:0010646	Cervical spine instability	Frequent (30-79%)
HP:0012230	Rhegmatogenous retinal detachment	Frequent (30-79%)
HP:0000201	Pierre-Robin sequence	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0002949	Fused cervical vertebrae	Occasional (5-29%)
HP:0003417	Coronal cleft vertebrae	Occasional (5-29%)
HP:0004557	Anterior vertebral fusion	Occasional (5-29%)
HP:0006375	Dumbbell-shaped femur	Occasional (5-29%)
HP:0006454	Delayed patellar ossification	Occasional (5-29%)
HP:0008422	Vertebral wedging	Occasional (5-29%)
HP:0012019	Lens luxation	Occasional (5-29%)
HP:0025474	Erythematous plaque	Occasional (5-29%)
HP:0000256	Macrocephaly	Very rare (<1-4%)
HP:0002086	Abnormality of the respiratory system	Very rare (<1-4%)
HP:0002176	Spinal cord compression	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Kniest dysplasia
Mondo ID	MONDO:0007987
MeSH	C537207
OMIM	156550
Orphanet	485
DOID	DOID:0080045
ICD-11	2088691719
NCIT	C125594
SNOMED CT	53974002
UMLS	C0265279
MedGen	75559
GARD	0006841
NORD	1339
Is cancer (heuristic)	no

Also known as: Kniest dysplasia

Data availability: 85 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 › Kniest dysplasia

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, pseudoachondroplasia, 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

85 retrieved; paginated sample, class counts are floors:

21 pathogenic, 16 conflicting classifications of pathogenicity, 16 likely pathogenic, 10 uncertain significance, 9 benign/likely benign, 8 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048782	NM_001844.5(COL2A1):c.1023+1G>C	COL2A1	Pathogenic	criteria provided, single submitter
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
1326875	NM_001844.5(COL2A1):c.1421_1426del (p.Gly474_Pro475del)	COL2A1	Pathogenic	criteria provided, single submitter
1326890	NM_001844.5(COL2A1):c.1068+1G>C	COL2A1	Pathogenic	criteria provided, single submitter
1332834	NM_001844.5(COL2A1):c.1680+2dup	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332845	NM_001844.5(COL2A1):c.1250G>T (p.Gly417Val)	COL2A1	Pathogenic	criteria provided, single submitter
1347701	NM_001844.5(COL2A1):c.1043G>A (p.Gly348Asp)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17362	NM_001844.5(COL2A1):c.906_924+9del	COL2A1	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
17369	NM_001844.5(COL2A1):c.1420-2A>G	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17370	NM_001844.5(COL2A1):c.908G>A (p.Gly303Asp)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17375	NM_001844.5(COL2A1):c.1266+1del	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
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
265429	NM_001844.5(COL2A1):c.2833G>A (p.Gly945Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2687874	NM_001844.5(COL2A1):c.1266+1G>T	COL2A1	Pathogenic	criteria provided, single submitter
2859637	NM_001844.5(COL2A1):c.3085G>T (p.Gly1029Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381842	NM_001844.5(COL2A1):c.1266+2T>A	COL2A1	Pathogenic	criteria provided, single submitter
3382704	NM_001844.5(COL2A1):c.970-2A>T	COL2A1	Pathogenic	criteria provided, single submitter
3382798	NM_001844.5(COL2A1):c.3040G>A (p.Gly1014Arg)	COL2A1	Pathogenic	criteria provided, single submitter
3721129	NM_001844.5(COL2A1):c.1223G>A (p.Gly408Asp)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449001	NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4685495	NM_001844.5(COL2A1):c.1997G>A (p.Gly666Glu)	COL2A1	Pathogenic	criteria provided, single submitter
988569	NM_001844.5(COL2A1):c.2059G>A (p.Gly687Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320320	NM_001844.5(COL2A1):c.1937dup (p.Ala647fs)	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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05408715	Not specified	RECRUITING	A Natural History Study in Children With a Type II Collagen Disorder With Short Stature