Varicose disease

Summary

Varicose disease (MONDO:0008638) is a disease with 4 cohort genes and 131 clinical trials. Top therapeutic interventions include dabigatran etexilate, dextrose, and polidocanol.

At a glance

• Cohort genes: 4
• ClinVar variants: 4
• Clinical trials: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	varicose disease
Mondo ID	MONDO:0008638
MeSH	D014648
OMIM	192200
DOID	DOID:799
NCIT	C35114
SNOMED CT	128060009
UMLS	C0042345
MedGen	21827
Is cancer (heuristic)	no

Also known as: varices · varicose veins · varix

Data availability: 4 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › vein disorder › varicose disease

Related subtypes (12): venous insufficiency, portal vein thrombosis, occlusion of tributary of retinal vein, central retinal vein occlusion, cavernous sinus meningioma, superior vena cava angiosarcoma, pulmonary vein leiomyosarcoma, phlebitis, malignant jugulotympanic paraganglioma, vein of Galen aneurysm, isolated splenic vein thrombosis, isolated mesenteric vein thrombosis

Subtypes (3): esophageal varices, pelvic varices, mesenteric varices

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

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
6559	NM_001171.6(ABCC6):c.3421C>T (p.Arg1141Ter)	ABCC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041456	NM_001851.6(COL9A1):c.964C>G (p.Pro322Ala)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
523433	NM_000501.4(ELN):c.898A>T (p.Thr300Ser)	ELN	Uncertain significance	criteria provided, multiple submitters, no conflicts
4819957	NM_001367624.2(ZNF469):c.10716C>A (p.Asp3572Glu)	ZNF469	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL9A1	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A1	Orphanet:250984	Autosomal recessive Stickler syndrome
ZNF469	Orphanet:90354	Brittle cornea syndrome
ELN	Orphanet:3193	Supravalvular aortic stenosis
ELN	Orphanet:90348	Autosomal dominant cutis laxa
ELN	Orphanet:904	Williams syndrome
ELN	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
ABCC6	Orphanet:51608	Generalized arterial calcification of infancy
ABCC6	Orphanet:758	Pseudoxanthoma elasticum

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL9A1	HGNC:2217	ENSG00000112280	P20849	Collagen alpha-1(IX) chain	clinvar
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	clinvar
ELN	HGNC:3327	ENSG00000049540	P15502	Elastin	clinvar
ABCC6	HGNC:57	ENSG00000091262	O95255	ATP-binding cassette sub-family C member 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL9A1	Collagen alpha-1(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
ZNF469	Zinc finger protein 469	May be involved in transcriptional regulation.
ELN	Elastin	Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely.
ABCC6	ATP-binding cassette sub-family C member 6	ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Transporter	1	19.4×	0.151
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL9A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469
ELN	Other/Unknown	no		Tropoelastin
ABCC6	Transporter	yes	7.6.2.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	2
tibia	2
ventricular zone	1
upper arm skin	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
duodenum	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL9A1	149	broad	marker	tibia, cartilage tissue, ventricular zone
ZNF469	211	broad	yes	tibia, upper arm skin, cartilage tissue
ELN	227	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
ABCC6	136		marker	right lobe of liver, liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELN	2,692
COL9A1	1,488
ZNF469	954
ABCC6	186

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL9A1	P20849	5
ABCC6	O95255	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ELN	P15502	36.20
ZNF469	Q96JG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCC6 causes PXE	1	3806.7×	0.004	ABCC6
ABC transporter disorders	1	146.4×	0.029	ABCC6
Elastic fibre formation	1	112.0×	0.029	ELN
Molecules associated with elastic fibres	1	102.9×	0.029	ELN
Collagen chain trimerization	1	86.5×	0.029	COL9A1
Signaling by PDGF	1	84.6×	0.029	COL9A1
NCAM1 interactions	1	82.8×	0.029	COL9A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.029	COL9A1
Collagen degradation	1	58.6×	0.029	COL9A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.029	COL9A1
ECM proteoglycans	1	50.1×	0.029	COL9A1
Disorders of transmembrane transporters	1	46.4×	0.029	ABCC6
Integrin cell surface interactions	1	44.8×	0.029	COL9A1
ABC-family protein mediated transport	1	40.5×	0.029	ABCC6
Degradation of the extracellular matrix	1	39.2×	0.029	ELN
Transport of small molecules	1	8.4×	0.122	ABCC6
Disease	1	4.4×	0.212	ABCC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
animal organ morphogenesis	2	95.8×	0.004	COL9A1, ELN
inorganic diphosphate transport	1	2106.5×	0.006	ABCC6
inhibition of non-skeletal tissue mineralization	1	1053.2×	0.008	ABCC6
leukotriene transport	1	601.9×	0.008	ABCC6
regulation of extracellular matrix organization	1	468.1×	0.008	ZNF469
response to sodium phosphate	1	421.3×	0.008	ABCC6
intracellular phosphate ion homeostasis	1	383.0×	0.008	ABCC6
ATP transport	1	351.1×	0.008	ABCC6
response to magnesium ion	1	351.1×	0.008	ABCC6
regulation of smooth muscle cell proliferation	1	324.1×	0.008	ELN
phosphate ion homeostasis	1	263.3×	0.009	ABCC6
extracellular matrix assembly	1	234.1×	0.009	ELN
stress fiber assembly	1	191.5×	0.010	ELN
respiratory gaseous exchange by respiratory system	1	156.0×	0.012	ELN
regulation of actin filament polymerization	1	145.3×	0.012	ELN
blood circulation	1	127.7×	0.013	ELN
ATP metabolic process	1	117.0×	0.013	ABCC6
calcium ion homeostasis	1	110.9×	0.013	ABCC6
aortic valve morphogenesis	1	108.0×	0.013	ELN
outflow tract morphogenesis	1	76.6×	0.017	ELN
skeletal muscle tissue development	1	72.6×	0.017	ELN
transmembrane transport	1	42.1×	0.028	ABCC6
gene expression	1	20.0×	0.053	ABCC6
visual perception	1	19.9×	0.053	ABCC6
response to xenobiotic stimulus	1	17.3×	0.059	ABCC6
negative regulation of transcription by RNA polymerase II	1	4.4×	0.207	ZNF469

Therapeutics

Drugs indicated for this disease

6 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Dextrose	Approved (phase 4)
Heparin	Approved (phase 4)
Pentosan Polysulfate Sodium	Approved (phase 4)
Phenol	Approved (phase 4)
Polidocanol	Approved (phase 4)
Sugar, Invert	Approved (phase 4)
Mucopolysaccharide Polysulfate	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Maritime Pine, Sodium Chloride.

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL9A1	0	0
ZNF469	0	0
ELN	0	0
ABCC6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ABCC6	10	Functional:9, Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCC6	7.6.2.3	ABC-type glutathione-S-conjugate transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	ABCC6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	COL9A1, ZNF469, ELN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL9A1	0	—
ZNF469	0	—
ELN	0	—
ABCC6	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 131.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	107
PHASE4	11
PHASE3	5
PHASE2	5
PHASE2/PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03416413	PHASE4	RECRUITING	Study of Foam Sclerotherapy Versus Ambulatory Phlebectomy
NCT05735639	PHASE4	RECRUITING	THRomboprophylaxis in Individuals Undergoing Superficial endoVEnous Treatment (THRIVE)
NCT01287702	PHASE4	UNKNOWN	Early Feeding Following Ligation of Acute Bleeding Varices
NCT01611324	PHASE4	COMPLETED	Painless Local Infiltration Anesthesia
NCT02010723	PHASE4	COMPLETED	Surgery Versus Sclerotherapy for Isolated Accessory Great Saphenous Vein Varicosis
NCT02054325	PHASE4	COMPLETED	Study Protocol Comparing Polidocanol Versus Hypertonic Glucose for Treatment of Reticular Veins
NCT02462720	PHASE4	COMPLETED	COMFORT: A Multicenter, Open-label, Randomized, Crossover Study
NCT02627846	PHASE4	COMPLETED	Laser Ablation Versus Mechanochemical Ablation Trial
NCT02657252	PHASE4	COMPLETED	Polidocanol Versus Glucose Treatment of Telangiectasia Trial
NCT02988063	PHASE4	WITHDRAWN	Effect of PEM Treatment of Superficial Axial and Tributary Vein Reflux on Improvement of Wound Healing in VLUs
NCT05312970	PHASE4	TERMINATED	Varithena Versus Endothermal Ablation of the Great Saphenous Vein (VERITAS)
NCT00500669	PHASE3	TERMINATED	A Randomised Study to Assess Betadine in the Groin Wound of Patients Undergoing Primary Varicose Vein Surgery
NCT00758420	PHASE2/PHASE3	COMPLETED	Randomized, Single Blind, Placebo Controlled, to Evaluate Efficacy and Safety of Polidocanol Injectable Foam for Treatment of Symptomatic, Visible Varicose Veins With SFJ Incompetence
NCT01072877	PHASE3	COMPLETED	Efficacy and Safety Study of Polidocanol Injectable Foam for the Treatment of Saphenofemoral Junction (SFJ) Incompetence
NCT01203397	PHASE3	WITHDRAWN	Safety And Efficacy Study Of Topic Mucopolysaccharide Polysulfate In The Superficial Varicose Veins Treatment
NCT01231373	PHASE3	COMPLETED	Polidocanol Endovenous Microfoam (PEM) Versus Vehicle for the Treatment of Saphenofemoral Junction (SFJ) Incompetence
NCT01426035	PHASE3	WITHDRAWN	Safety And Efficacy Study Of Topic Mucopolysaccharide Polysulfate Cream In The Superficial Varicose Veins Treatment
NCT05511766	PHASE2/PHASE3	UNKNOWN	Allopurinol Versus Atorvastatin to Prevent Complications of Liver Cirrhosis
NCT00430326	PHASE2	COMPLETED	Juvista (Avotermin) in Scars Following Varicose Vein Removal
NCT00442364	PHASE2	COMPLETED	Safety Study of Varisolve® Procedure for Treatment of Varicose Veins in Patients With Right-to-left Cardiac Shunt
NCT00928421	PHASE2	COMPLETED	An Open-label, Single-dose Pilot Study to Evaluate Varisolve® (Polidocanol Endovenous Microfoam (PEM)) 0.125% [0.2%] for Varicose Veins
NCT02139085	PHASE2	UNKNOWN	Great Saphenous Vein Electrocoagulation
NCT04203043	PHASE2	UNKNOWN	The Prevstain Trial
NCT01428076	PHASE1	COMPLETED	Pharmacokinetic Study of Polidocanol Endovenous Microfoam (PEM)
NCT02397226	Not specified	ACTIVE_NOT_RECRUITING	Lower Limb Venous Insufficiency and the Effect of Radiofrequency Treatment Versus Open Surgery
NCT03041805	Not specified	RECRUITING	Caprini Score in Venous Surgery: a Prospective Cohort Study
NCT04231942	Not specified	ACTIVE_NOT_RECRUITING	Elastic Compression Stockings and Varicose Veins Recurrence
NCT05410912	Not specified	ACTIVE_NOT_RECRUITING	Varicose Vein in Patients Under the Age of 40
NCT05663359	Not specified	RECRUITING	Study on Treatment of Varicose Veins by Endovenous Laser (1940 nm vs 1470 nm)
NCT06367166	Not specified	ACTIVE_NOT_RECRUITING	Effects of Bioflavanoids on Vascular Wall Remodeling in Patients With Varicose Veins
NCT06456125	Not specified	ACTIVE_NOT_RECRUITING	Safety and Efficacy Of Amber Peripheral Liquid Embolic System
NCT06669260	Not specified	NOT_YET_RECRUITING	Evaluating QoL and Postoperative Complications Using TEThA Technique in the Treatment of Tributary Veins
NCT06971068	Not specified	RECRUITING	Vacuum-assisted Laser Ablation (VALA) for Treatment of Large Saphenous Veins
NCT07276243	Not specified	RECRUITING	Polidocanol Foam With or Without Transdermal Laser in Varicose Veins
NCT07449728	Not specified	RECRUITING	The Influence of Laser Crossectomy With Different Wavelengths on Varicose Vein Progression
NCT07570277	Not specified	RECRUITING	Research on the Application of Nursing Intervention Based on ITHBC Theory in Postoperative Self-Management of Patients With Varicose Veins of the Lower Extremities
NCT00618514	Not specified	TERMINATED	The BRILLIANT Study
NCT00621062	Not specified	COMPLETED	Prospective Randomized Trial Comparing the New Endovenous Procedures Versus Conventional Surgery for Varicose Veins Due to Great Saphenous Vein Incompetence
NCT00702897	Not specified	UNKNOWN	Ambulatory Surgery of Lower Extremity Varicose Vein
NCT00759434	Not specified	COMPLETED	A New Method of Surgically Treating Varicose Veins and Venous Ulcers - a Study to Assess Clinical and Economic Value

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DABIGATRAN ETEXILATE	4	3
DEXTROSE	4	2
POLIDOCANOL	4	2
ALLOPURINOL	4	1
APIXABAN	4	1
DALTEPARIN SODIUM	4	1
DIOSMIN	4	1
ENOXAPARIN SODIUM	4	1
POVIDONE-IODINE	4	1
RIVAROXABAN	4	1
SODIUM BICARBONATE	4	1
SODIUM TETRADECYL SULFATE	4	1
TINZAPARIN SODIUM	4	1
AVOTERMIN	3	1
HESPERIDIN	3	1
MARITIME PINE	3	1
MECRYLATE	3	1
SOMATOSTATIN	3	1
CHEMBL1231723	0	2
VEHICLE	0	2
CHEMBL3039392	0	1
SCEPTRIN	0	1