Aortic valve disease 3

Summary

Aortic valve disease 3 (MONDO:0032783) is a disease caused by ROBO4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ROBO4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic valve disease 3
Mondo ID	MONDO:0032783
OMIM	618496
DOID	DOID:0080977
UMLS	C5193127
MedGen	1681142
GARD	0025742
Is cancer (heuristic)	no

Also known as: AOVD3

Data availability: 29 ClinVar variants · 4 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 3

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

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

29 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 5 conflicting classifications of pathogenicity, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333606	NM_019055.6(ROBO4):c.1146C>G (p.Tyr382Ter)	ROBO4	Likely pathogenic	criteria provided, single submitter
2441673	NM_019055.6(ROBO4):c.980_981del (p.Ser327fs)	ROBO4	Likely pathogenic	criteria provided, single submitter
3393140	NM_019055.6(ROBO4):c.1042_1048dup	ROBO4	Likely pathogenic	criteria provided, single submitter
3780562	NM_019055.6(ROBO4):c.2041del (p.Leu681fs)	ROBO4	Likely pathogenic	criteria provided, single submitter
560404	NM_019055.6(ROBO4):c.2056+1G>T	ROBO4	Likely pathogenic	criteria provided, single submitter
1284937	NM_019055.6(ROBO4):c.1985G>A (p.Gly662Asp)	ROBO4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805002	NM_019055.6(ROBO4):c.1900C>T (p.Arg634Cys)	ROBO4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560394	NM_019055.6(ROBO4):c.190C>T (p.Arg64Cys)	ROBO4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560396	NM_019055.6(ROBO4):c.695C>T (p.Thr232Met)	ROBO4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560398	NM_019055.6(ROBO4):c.1702C>T (p.Arg568Ter)	ROBO4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328436	NM_019055.6(ROBO4):c.691T>A (p.Tyr231Asn)	ROBO4	Uncertain significance	no assertion criteria provided
1676230	NM_019055.6(ROBO4):c.1471C>T (p.Arg491Cys)	ROBO4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1804989	NM_019055.6(ROBO4):c.1678C>T (p.Arg560Cys)	ROBO4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2353403	NM_019055.6(ROBO4):c.2171C>T (p.Thr724Ile)	ROBO4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435453	NM_019055.6(ROBO4):c.184A>G (p.Thr62Ala)	ROBO4	Uncertain significance	criteria provided, single submitter
2435454	NM_019055.6(ROBO4):c.2182C>T (p.Gln728Ter)	ROBO4	Uncertain significance	criteria provided, single submitter
2585562	NM_019055.6(ROBO4):c.2758G>A (p.Gly920Ser)	ROBO4	Uncertain significance	criteria provided, single submitter
3024526	NM_019055.6(ROBO4):c.746T>C (p.Leu249Pro)	ROBO4	Uncertain significance	criteria provided, single submitter
3236629	NM_019055.6(ROBO4):c.2092C>A (p.Leu698Met)	ROBO4	Uncertain significance	criteria provided, single submitter
3434744	NM_019055.6(ROBO4):c.1241G>C (p.Gly414Ala)	ROBO4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599132	NM_019055.6(ROBO4):c.1235T>C (p.Met412Thr)	ROBO4	Uncertain significance	criteria provided, single submitter
3599134	NM_019055.6(ROBO4):c.911G>A (p.Gly304Asp)	ROBO4	Uncertain significance	criteria provided, single submitter
3780563	NM_019055.6(ROBO4):c.2896del (p.Val966fs)	ROBO4	Uncertain significance	criteria provided, single submitter
3892310	NM_019055.6(ROBO4):c.1064C>T (p.Thr355Ile)	ROBO4	Uncertain significance	criteria provided, single submitter
3892311	NM_019055.6(ROBO4):c.1087G>C (p.Val363Leu)	ROBO4	Uncertain significance	criteria provided, single submitter
3892312	NM_019055.6(ROBO4):c.2723G>A (p.Arg908Gln)	ROBO4	Uncertain significance	criteria provided, single submitter
4156056	NM_019055.6(ROBO4):c.1474C>T (p.Arg492Trp)	ROBO4	Uncertain significance	criteria provided, multiple submitters, no conflicts
4526491	NM_019055.6(ROBO4):c.588dup (p.Ala197fs)	ROBO4	Uncertain significance	criteria provided, single submitter
4531814	NM_019055.6(ROBO4):c.1825_1829del (p.Pro609fs)	ROBO4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ROBO4	Strong	Autosomal dominant	aortic valve disease 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROBO4	Orphanet:402075	Familial bicuspid aortic valve

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
ROBO4	HGNC:17985	ENSG00000154133	Q8WZ75	Roundabout homolog 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROBO4	Roundabout homolog 4	Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ROBO4	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_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
apex of heart	1
lower lobe of lung	1
omental fat pad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROBO4	254	broad	marker	lower lobe of lung, apex of heart, omental fat pad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ROBO4	1,407

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ROBO4	Q8WZ75	57.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
blood vessel endothelial cell migration	1	1404.3×	0.003	ROBO4
dendrite self-avoidance	1	1053.2×	0.003	ROBO4
establishment of endothelial barrier	1	766.0×	0.003	ROBO4
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.003	ROBO4
regulation of cell migration	1	157.5×	0.009	ROBO4
homophilic cell-cell adhesion	1	140.4×	0.009	ROBO4
axon guidance	1	90.6×	0.013	ROBO4
angiogenesis	1	62.4×	0.016	ROBO4

Therapeutics

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
ROBO4	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	1	ROBO4
E	Difficult family or no structure, no drug	0

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)
ROBO4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.