Aortic valve insufficiency

Summary

Aortic valve insufficiency (MONDO:0005648) is a disease with 1 cohort gene and 83 clinical trials. Top therapeutic interventions include isoflurane, metoprolol, and warfarin.

At a glance

• Cohort genes: 1
• ClinVar variants: 2
• Clinical trials: 83

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic valve insufficiency
Mondo ID	MONDO:0005648
EFO	EFO:0007148
MeSH	D001022
DOID	DOID:57
ICD-10-CM	I06.1
ICD-11	1548485475
NCIT	C51223
SNOMED CT	78031003
UMLS	C0003504
MedGen	8153
Anatomy (UBERON)	UBERON:0002137
Is cancer (heuristic)	no

Also known as: aortic insufficiency · rheumatic aortic insufficiency · rheumatic aortic regurgitation

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › aortic valve disorder › aortic valve insufficiency

Related subtypes (4): aortic valve calcification, aortic valve prolapse, familial bicuspid aortic valve, aortic valve stenosis

Subtypes (1): congenital aortic valve insufficiency

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

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267941	46;XY;inv(6)(p22q13)dn		Pathogenic	criteria provided, single submitter
200029	NM_000138.5(FBN1):c.139G>A (p.Gly47Ser)	FBN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia

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
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective 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)
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
decidua	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Elastic fibre formation	1	335.9×	0.008	FBN1
TGF-beta receptor signaling activates SMADs	1	326.3×	0.008	FBN1
Molecules associated with elastic fibres	1	308.6×	0.008	FBN1
Integrin cell surface interactions	1	134.3×	0.012	FBN1
Degradation of the extracellular matrix	1	117.7×	0.012	FBN1
Post-translational protein phosphorylation	1	100.2×	0.012	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	FBN1

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
post-embryonic eye morphogenesis	1	5617.3×	0.001	FBN1
obsolete sequestering of BMP in extracellular matrix	1	4213.0×	0.001	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	4213.0×	0.001	FBN1
negative regulation of osteoclast development	1	3370.4×	0.001	FBN1
embryonic eye morphogenesis	1	1532.0×	0.002	FBN1
cellular response to insulin-like growth factor stimulus	1	1296.3×	0.002	FBN1
cell adhesion mediated by integrin	1	674.1×	0.004	FBN1
negative regulation of osteoclast differentiation	1	543.6×	0.004	FBN1
metanephros development	1	510.7×	0.004	FBN1
camera-type eye development	1	358.6×	0.004	FBN1
lung alveolus development	1	351.1×	0.004	FBN1
cellular response to transforming growth factor beta stimulus	1	276.3×	0.005	FBN1
glucose metabolic process	1	255.3×	0.005	FBN1
glucose homeostasis	1	130.6×	0.009	FBN1
skeletal system development	1	125.8×	0.009	FBN1
gene expression	1	79.9×	0.013	FBN1
heart development	1	78.8×	0.013	FBN1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Amlodipine, Losartan, Sacubitril, Valsartan.

Drug target analysis

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

Druggability breadth: 0 of 1 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
FBN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	FBN1

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)
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 83.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	73
PHASE4	3
PHASE3	3
PHASE2	2
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01157572	PHASE4	COMPLETED	Effect of Beta Blockade on Left Ventricular Remodeling and Function in Moderate to Severe Asymptomatic Aortic Regurgitation
NCT01201070	PHASE4	UNKNOWN	Study of Administration Of Antithrombin in Patients With Low Plasmatic Levels of Antithrombin After Cardiac Surgery
NCT03807921	PHASE4	COMPLETED	Anticoagulation for Aortic Bioprosthesis (ANTIPRO)
NCT00478803	PHASE3	COMPLETED	Conservative Aortic Valve Surgery for Aortic Insufficiency and Aneurysms of the Aortic Root. CAVIAAR
NCT01115907	PHASE3	COMPLETED	Freedom SOLO Stentless Heart Valve Study
NCT05696509	PHASE3	COMPLETED	Influence of Anesthetics on Clinical Outcome in Mitral and Aortic Valve Replacement in Adults
NCT00082121	PHASE2	COMPLETED	Safety and Efficacy of TP10, a Complement Inhibitor, in Adult Women Undergoing Cardiopulmonary Bypass Surgery
NCT05212597	PHASE2	UNKNOWN	Open Label RCT for Chronic Severe AR : Entresto vs. CCB/ARB
NCT05695287	PHASE1	COMPLETED	The Effects of Sevoflurane, Isoflurane and Propofol During Cardiac Surgery
NCT05742789	PHASE1	COMPLETED	Effect of Anesthetics on Troponin I and С-reactive Protein
NCT03728049	Not specified	RECRUITING	Von Willebrand Factor Point-of-care Testing to Improve Minimally Invasive TAVI Outcomes
NCT03826264	Not specified	RECRUITING	Transpacific TAVR Registry
NCT04149600	Not specified	ACTIVE_NOT_RECRUITING	Identification of Genetic Causes of Calcific Aortic Valve Disease
NCT04162444	Not specified	RECRUITING	Results of the Aortic Valve Reconstruction in Children
NCT04281771	Not specified	ACTIVE_NOT_RECRUITING	Assessment of Paravalvular Leak After TAVI by Hemodynamic Measurements and Cardiac MRI
NCT04415047	Not specified	ACTIVE_NOT_RECRUITING	The JenaValve ALIGN-AR Pivotal Trial
NCT05172973	Not specified	RECRUITING	ALLIANCE AVIV: Safety and Effectiveness of the SAPIEN X4 Transcatheter Heart Valve in Failing Aortic Bioprosthetic Valves
NCT05295628	Not specified	ACTIVE_NOT_RECRUITING	Evaluation of Safety and Effectiveness of the EMBLOK EPS During TAVR
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05572710	Not specified	RECRUITING	Avalus European Registry - an Observational Study to Evaluate Safety and Efficacy in a Real World Population
NCT05714293	Not specified	ENROLLING_BY_INVITATION	CT-evaluation of Coronary Ostia Height After Surgical Aortic Valve Replacement.
NCT05927090	Not specified	ENROLLING_BY_INVITATION	Outcomes of Aortic Dissection Repair
NCT06034028	Not specified	ACTIVE_NOT_RECRUITING	J-Valve TF Early Feasibility Study
NCT06235385	Not specified	RECRUITING	European Association of Cardiovascular Imaging Multiple and Mixed Valvular Disease Study
NCT06377449	Not specified	RECRUITING	Influence of Lung Ultrasonography on the Prognosis and Postoperative Outcomes in Cardiac Surgical Patients
NCT06420895	Not specified	ACTIVE_NOT_RECRUITING	Health Data Warehouse on Aortic Insufficiency
NCT06594705	Not specified	RECRUITING	The JenaValve ALIGN-AR LVAD Registry
NCT06608823	Not specified	RECRUITING	ARTIST: Aortic Regurgitation Trial Investigating Surgery Versus Trilogy™
NCT06835946	Not specified	RECRUITING	Impact of Anesthesia, Positive Pressure Ventilation and Modality of Imaging on the Echocardiographic Assessment of the Severity of Aortic Regurgitation
NCT06953206	Not specified	NOT_YET_RECRUITING	Prospective, Long-term Evaluation of the SAPIEN 3 Ultra RESILIA Valve
NCT07068633	Not specified	NOT_YET_RECRUITING	Korea VHD Echo Study: Surveillance of Aortic, Mitral & Tricuspid Patients - Insights From Real-world Practice
NCT07251660	Not specified	NOT_YET_RECRUITING	Comparison of Early Postoperative Outcomes Between Minimally Invasive Valve Surgery Via Right Thoracotomy and Conventional Valve Surgery Via Sternotomy.
NCT07363473	Not specified	NOT_YET_RECRUITING	JOURNEY LVAD: JOURNEY Left Ventricular Assist Device
NCT07453407	Not specified	RECRUITING	ART Trial: Transcatheter J-VALVE Versus Surgery for Aortic Regurgitation Therapy
NCT00001314	Not specified	COMPLETED	Investigation of Heart Function in Patients With Heart Valve Defects
NCT00173186	Not specified	UNKNOWN	Aortic Regurgitation After Surgical Repair of Outlet-Type Ventricular Septal Defect
NCT00475267	Not specified	COMPLETED	Aortic Valve Replacement With Trifecta(TM)
NCT00475709	Not specified	COMPLETED	Aortic Valve Replacement With Trifecta(TM)
NCT00598598	Not specified	TERMINATED	Echocardiographic Assessment of Cardiovascular Changes in Long Term Space Flight
NCT00598754	Not specified	WITHDRAWN	Diagnostic Three Dimensional Echocardiography Study Protocol

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ISOFLURANE	4	3
METOPROLOL	4	2
WARFARIN	4	1
ANTITHROMBIN III HUMAN	3	1