Avascular necrosis of femoral head, primary, 1

Summary

Avascular necrosis of femoral head, primary, 1 (MONDO:0054550) is a disease caused by COL2A1 (GenCC Strong), with 1 cohort gene and 18 clinical trials. Top therapeutic interventions include desflurane.

At a glance

• Causal gene: COL2A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 61
• Clinical trials: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	avascular necrosis of femoral head, primary, 1
Mondo ID	MONDO:0054550
OMIM	608805
UMLS	C4551562
MedGen	1639295
GARD	0025946
Is cancer (heuristic)	no

Also known as: ANFH1 · avascular necrosis of femoral head, primary, 1 · avascular necrosis of the femoral head · ischaemic necrosis of femoral head

Data availability: 61 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › avascular necrosis › primary avascular necrosis › familial avascular necrosis of femoral head › avascular necrosis of femoral head, primary, 1

Related subtypes (1): avascular necrosis of femoral head, primary, 2

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

61 retrieved; paginated sample, class counts are floors:

15 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 pathogenic, 9 benign/likely benign, 7 uncertain significance, 6 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
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702527	NM_001844.5(COL2A1):c.1862G>A (p.Gly621Glu)	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
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
17394	NM_001844.5(COL2A1):c.2149G>A (p.Gly717Ser)	COL2A1	Pathogenic	no assertion criteria provided
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
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
1516689	NM_001844.5(COL2A1):c.1618G>A (p.Gly540Ser)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698798	NM_001844.5(COL2A1):c.2748CCCTGGTCC[3] (p.Pro922_Ser923insProGlyPro)	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
3574632	NM_001844.5(COL2A1):c.1529G>T (p.Gly510Val)	COL2A1	Likely pathogenic	criteria provided, single submitter
3574633	NM_001844.5(COL2A1):c.1365+3A>C	COL2A1	Likely pathogenic	criteria provided, single submitter
3574634	NM_001844.5(COL2A1):c.917_918delinsA (p.Gly306fs)	COL2A1	Likely pathogenic	criteria provided, single submitter
4796517	NM_001844.5(COL2A1):c.2464-2A>T	COL2A1	Likely pathogenic	criteria provided, single submitter
4796588	NM_001844.5(COL2A1):c.2957C>T (p.Pro986Leu)	COL2A1	Likely pathogenic	criteria provided, single submitter
1003871	NM_001844.5(COL2A1):c.1057G>A (p.Ala353Thr)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011511	NM_001844.5(COL2A1):c.2947G>A (p.Val983Ile)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019069	NM_001844.5(COL2A1):c.4348A>G (p.Ile1450Val)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020209	NM_001844.5(COL2A1):c.3007G>A (p.Glu1003Lys)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386179	NM_001844.5(COL2A1):c.1757G>A (p.Arg586His)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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	dysplasia of the proximal femoral epiphyses	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: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	16
PHASE4	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03639532	PHASE4	COMPLETED	Ceramic-on-Ceramic Versus Ceramic-on-HXLPE THA
NCT02065167	PHASE2	COMPLETED	Evaluation of Mesenchymal Stem Cells to Treat Avascular Necrosis of the Hip
NCT02748408	Not specified	RECRUITING	The Medacta International SMS Post-Marketing Surveillance Study
NCT04731077	Not specified	ACTIVE_NOT_RECRUITING	Avenir Complete Post-Market Clinical Follow-Up Study
NCT04997005	Not specified	ACTIVE_NOT_RECRUITING	The Medacta International AMIStem-P Post-Marketing Surveillance Study
NCT05186168	Not specified	ACTIVE_NOT_RECRUITING	Corin MiniHip and Trinity Cup Clinical Surveillance Study
NCT05227924	Not specified	RECRUITING	Safety and Performance Assessment of the SYMBOL Range of Medical Devices in Patients Underlying Total Hip Arthroplasty
NCT05460715	Not specified	ACTIVE_NOT_RECRUITING	The Medacta Quadra-P Anteverted Study
NCT06123481	Not specified	RECRUITING	Autologous Bone Marrow Aspirate Treatment for Early-Stage Osteonecrosis
NCT06631638	Not specified	RECRUITING	EMPHASYS Cup Positioning in THA With Non-Invasive Navigation (Velys Hip Navigation (VHN))
NCT06772558	Not specified	NOT_YET_RECRUITING	Desflurane Potentially Induces Postoperative Cognitive Dysfunction in Elderly Patients Undergoing Perioperative Procedures by Modulating Cdc42 and Clock Proteins
NCT07104279	Not specified	RECRUITING	Z1 Hip System: Post-Market Clinical Follow Up Study
NCT01643655	Not specified	COMPLETED	Autologous Adipose Tissue Derived Mesenchymal Stem Cells Transplantation in Patient With Avascular Necrosis of the Femoral Head
NCT02552069	Not specified	UNKNOWN	Tritanium® Study in Japan
NCT02662881	Not specified	UNKNOWN	Biologically Assisted Core Decompression of the Femoral Head Using the PerFuse Instrument and BioCUE
NCT02783274	Not specified	COMPLETED	Actis Total Hip System 2 Year Follow-up
NCT03753282	Not specified	WITHDRAWN	Outcome After Avascular Necrosis of the Femoral Head in Young Patients
NCT05982054	Not specified	COMPLETED	Bone Marrow Cells With Core Decompression for AVN Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DESFLURANE	4	1