Aortic valve disease 2

Summary

Aortic valve disease 2 (MONDO:0013902) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 1,254

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic valve disease 2
Mondo ID	MONDO:0013902
OMIM	614823
DOID	DOID:0080334
UMLS	C3542024
MedGen	762200
GARD	0018471
Is cancer (heuristic)	no

Also known as: aortic valve disease 2 · aortic valve disease caused by mutation in SMAD6 · aortic valve disease type 2 · AOVD2 · SMAD6 aortic valve disease

Data availability: 1,254 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › aortic valve disorder › familial bicuspid aortic valve › aortic valve disease 2

Related subtypes (2): aortic valve disease 1, aortic valve disease 3

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

600 retrieved; paginated sample, class counts are floors:

303 uncertain significance, 202 likely benign, 31 conflicting classifications of pathogenicity, 30 pathogenic, 16 benign/likely benign, 8 benign, 6 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174564	NM_005585.5(SMAD6):c.232_250del (p.Gln78fs)	SMAD6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1315797	NM_005585.5(SMAD6):c.792C>A (p.Tyr264Ter)	SMAD6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342165	NM_005585.5(SMAD6):c.652C>T (p.Gln218Ter)	SMAD6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012346	NM_181486.4(TBX5):c.652C>T (p.Gln218Ter)	TBX5	Pathogenic	criteria provided, single submitter
1062314	NM_181486.4(TBX5):c.252T>A (p.Phe84Leu)	TBX5	Pathogenic	criteria provided, single submitter
1068185	NM_181486.4(TBX5):c.511-1G>C	TBX5	Pathogenic	criteria provided, single submitter
1071824	NM_181486.4(TBX5):c.383_386dup (p.Met131fs)	TBX5	Pathogenic	criteria provided, single submitter
1071999	NM_181486.4(TBX5):c.243-2A>G	TBX5	Pathogenic	criteria provided, single submitter
1072954	NM_181486.4(TBX5):c.765T>A (p.Tyr255Ter)	TBX5	Pathogenic	criteria provided, single submitter
1075045	NM_181486.4(TBX5):c.341dup (p.Tyr114Ter)	TBX5	Pathogenic	criteria provided, single submitter
1076612	NC_000012.11:g.(?114793327)(114793921_?)del	TBX5	Pathogenic	criteria provided, single submitter
1350538	NM_181486.4(TBX5):c.760G>T (p.Glu254Ter)	TBX5	Pathogenic	criteria provided, single submitter
1409261	NM_181486.4(TBX5):c.982+1G>A	TBX5	Pathogenic	criteria provided, single submitter
1453432	NM_181486.4(TBX5):c.400del (p.Arg134fs)	TBX5	Pathogenic	criteria provided, single submitter
1454149	NM_181486.4(TBX5):c.1012del (p.Tyr338fs)	TBX5	Pathogenic	criteria provided, single submitter
1454646	NM_181486.4(TBX5):c.1037C>A (p.Ser346Ter)	TBX5	Pathogenic	criteria provided, single submitter
1455790	NM_181486.4(TBX5):c.982+2T>G	TBX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457204	NC_000012.11:g.(?114823261)(114823392_?)del	TBX5	Pathogenic	criteria provided, single submitter
1459610	NC_000012.11:g.(?114837390)(114846189_?)del	TBX5	Pathogenic	criteria provided, single submitter
1470937	NM_181486.4(TBX5):c.755+1G>T	TBX5	Pathogenic	criteria provided, single submitter
2016615	NM_181486.4(TBX5):c.853_865del (p.Ser285fs)	TBX5	Pathogenic	criteria provided, single submitter
2050129	NM_181486.4(TBX5):c.755+1G>A	TBX5	Pathogenic	criteria provided, single submitter
2075482	NM_181486.4(TBX5):c.148-2A>C	TBX5	Pathogenic	criteria provided, single submitter
213820	NM_181486.4(TBX5):c.142C>T (p.Gln48Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
213830	NM_181486.4(TBX5):c.611dup (p.His204fs)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
213832	NM_181486.4(TBX5):c.835C>T (p.Arg279Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
237218	NM_181486.4(TBX5):c.958del (p.Ile320fs)	TBX5	Pathogenic	criteria provided, single submitter
2422562	NC_000012.11:g.(?114793337)(114837457_?)del	TBX5	Pathogenic	criteria provided, single submitter
2422563	NC_000012.11:g.(?114803950)(114804216_?)dup	TBX5	Pathogenic	criteria provided, single submitter
2697016	NM_181486.4(TBX5):c.594dup (p.Thr199fs)	TBX5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · 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
SMAD6	Moderate	Autosomal dominant	aortic valve disease 2	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD6	Orphanet:402075	Familial bicuspid aortic valve
TBX3	Orphanet:3138	Ulnar-mammary syndrome
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	gencc,clinvar
TBX3	HGNC:11602	ENSG00000135111	O15119	T-box transcription factor TBX3	clinvar
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.
TBX3	T-box transcription factor TBX3	Transcriptional repressor involved in developmental processes.
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Transcription factor	2	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
TBX3	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
right lung	1
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1
buccal mucosa cell	1
cardiac muscle of right atrium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus
TBX3	243	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX3	2,379
TBX5	2,250
SMAD6	2,006

Intra-cohort edges

A	B	Sources
TBX3	TBX5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBX5	Q99593	4
TBX3	O15119	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMAD6	O43541	72.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 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
RUNX2 regulates bone development	1	271.9×	0.021	SMAD6
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	253.8×	0.021	TBX5
Physiological factors	1	223.9×	0.021	TBX5
Cardiogenesis	1	141.0×	0.021	TBX5
Signaling by BMP	1	119.0×	0.021	SMAD6
RNA Polymerase II Transcription	2	15.0×	0.021	SMAD6, TBX5
Gene expression (Transcription)	2	11.9×	0.021	SMAD6, TBX5
Transcriptional regulation by RUNX2	1	84.6×	0.022	SMAD6
Generic Transcription Pathway	2	10.1×	0.022	SMAD6, TBX5
Developmental Biology	2	9.6×	0.022	TBX3, TBX5
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.024	TBX3
Signaling by TGFB family members	1	38.5×	0.031	SMAD6
MITF-M-regulated melanocyte development	1	38.1×	0.031	TBX3
Cardiac conduction	1	36.2×	0.031	TBX5
Muscle contraction	1	25.7×	0.041	TBX5
Signal Transduction	1	3.4×	0.267	SMAD6

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
atrioventricular bundle cell differentiation	2	3744.9×	7e-06	TBX3, TBX5
forelimb morphogenesis	2	1404.3×	3e-05	TBX3, TBX5
cell fate specification	2	351.1×	3e-04	TBX3, TBX5
ventricular septum development	2	330.4×	3e-04	SMAD6, TBX5
embryonic forelimb morphogenesis	2	330.4×	3e-04	TBX3, TBX5
mesoderm morphogenesis	1	5617.3×	0.002	TBX3
cell migration involved in coronary vasculogenesis	1	5617.3×	0.002	TBX5
positive regulation of cardiac conduction	1	5617.3×	0.002	TBX5
negative regulation of cell proliferation involved in heart morphogenesis	1	5617.3×	0.002	TBX3
cardiac left ventricle formation	1	2808.7×	0.002	TBX5
limbic system development	1	2808.7×	0.002	TBX3
follicle-stimulating hormone secretion	1	2808.7×	0.002	TBX3
atrioventricular node cell fate commitment	1	2808.7×	0.002	TBX5
hepatoblast differentiation	1	2808.7×	0.002	TBX3
ureteric peristalsis	1	2808.7×	0.002	TBX3
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	2808.7×	0.002	TBX5
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	2808.7×	0.002	TBX5
zygotic specification of dorsal/ventral axis	1	1872.4×	0.003	SMAD6
specification of animal organ position	1	1872.4×	0.003	TBX3
mammary placode formation	1	1872.4×	0.003	TBX3
positive regulation of secondary heart field cardioblast proliferation	1	1872.4×	0.003	TBX5
cardiac jelly development	1	1872.4×	0.003	TBX3
bundle of His development	1	1404.3×	0.003	TBX5
luteinizing hormone secretion	1	1404.3×	0.003	TBX3
response to laminar fluid shear stress	1	1404.3×	0.003	SMAD6
positive regulation of cardioblast differentiation	1	1404.3×	0.003	TBX5
atrioventricular node cell development	1	1404.3×	0.003	TBX5
atrioventricular canal morphogenesis	1	1404.3×	0.003	TBX3
regulation of transcription by RNA polymerase II	3	11.7×	0.003	SMAD6, TBX3, TBX5
cardiac muscle cell fate commitment	1	1123.5×	0.003	TBX3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD6	0	0
TBX3	0	0
TBX5	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
TBX5	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	SMAD6, TBX3, TBX5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD6	0	—
TBX3	0	—
TBX5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.