Vesicoureteral reflux 8

Summary

Vesicoureteral reflux 8 (MONDO:0014422) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 212

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vesicoureteral reflux 8
Mondo ID	MONDO:0014422
OMIM	615963
UMLS	C4014831
MedGen	863268
GARD	0018425
Is cancer (heuristic)	no

Also known as: TNXB vesicoureteral reflux (disease) · vesicoureteral reflux (disease) caused by mutation in TNXB · vesicoureteral reflux 8 · vesicoureteral reflux type 8 · VUR8

Data availability: 212 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial vesicoureteral reflux › vesicoureteral reflux 8

Related subtypes (8): vesicoureteral reflux 1, vesicoureteral reflux, X-linked, vesicoureteral reflux 2, vesicoureteral reflux 3, vesicoureteral reflux 4, vesicoureteral reflux 5, vesicoureteral reflux 6, vesicoureteral reflux 7

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

212 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 48 conflicting classifications of pathogenicity, 42 likely pathogenic, 19 benign/likely benign, 13 pathogenic/likely pathogenic, 11 benign, 4 likely benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3593443	NM_001365276.2(TNXB):c.12559C>T (p.Arg4187Ter)	LOC106780803	Pathogenic	criteria provided, single submitter
2434194	NM_001365276.2(TNXB):c.10291C>T (p.Arg3431Ter)	LOC126859654	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323700	NM_001365276.2(TNXB):c.7826-1G>C	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323701	NM_001365276.2(TNXB):c.8411del (p.Leu2804fs)	TNXB	Pathogenic	criteria provided, single submitter
1326137	NM_001365276.2(TNXB):c.6293dup (p.Glu2100fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144114	NM_001365276.2(TNXB):c.3991G>A (p.Gly1331Arg)	TNXB	Pathogenic	no assertion criteria provided
1702327	NM_001365276.2(TNXB):c.3942dup (p.Thr1315fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805011	NM_001365276.2(TNXB):c.3763dup (p.Arg1255fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2392339	NM_001365276.2(TNXB):c.8613del (p.Phe2871fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384708	NM_001365276.2(TNXB):c.3907C>T (p.Gln1303Ter)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593460	NM_001365276.2(TNXB):c.7505del (p.Asp2502fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593470	NM_001365276.2(TNXB):c.4706_4707del (p.Thr1569fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593471	NM_001365276.2(TNXB):c.4411del (p.Ser1471fs)	TNXB	Pathogenic	criteria provided, single submitter
3593481	NM_001365276.2(TNXB):c.703_704dup (p.Arg236fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521427	NM_001365276.2(TNXB):c.1878del (p.His626fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8550	NM_001365276.2(TNXB):c.3290_3291del (p.Lys1097fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871711	NM_001365276.2(TNXB):c.3288del (p.Gln1095_Tyr1096insTer)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593445	NM_001365276.2(TNXB):c.12180C>A (p.Cys4060Ter)	LOC106780803	Likely pathogenic	criteria provided, single submitter
3593446	NM_001365276.2(TNXB):c.11485C>T (p.Arg3829Ter)	LOC106780803	Likely pathogenic	criteria provided, single submitter
3593449	NM_001365276.2(TNXB):c.10765C>T (p.Gln3589Ter)	LOC106780803	Likely pathogenic	criteria provided, single submitter
1325210	NM_001365276.2(TNXB):c.9758-2_9758-1del	TNXB	Likely pathogenic	criteria provided, single submitter
1325211	NM_001365276.2(TNXB):c.1650_1651del (p.Glu552fs)	TNXB	Likely pathogenic	criteria provided, single submitter
1325212	NM_001365276.2(TNXB):c.8473G>A (p.Glu2825Lys)	TNXB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325213	NM_001365276.2(TNXB):c.5882_5883del (p.Val1961fs)	TNXB	Likely pathogenic	criteria provided, single submitter
1702298	NM_001365276.2(TNXB):c.10623_10624del (p.Pro3542fs)	TNXB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690767	NM_001365276.2(TNXB):c.200_208delinsTGGAAGG (p.Gly67fs)	TNXB	Likely pathogenic	criteria provided, single submitter
3343873	NM_001365276.2(TNXB):c.9116-1G>A	TNXB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593444	NM_001365276.2(TNXB):c.12240_12243del (p.Asp4081fs)	TNXB	Likely pathogenic	criteria provided, single submitter
3593447	NM_001365276.2(TNXB):c.11387-2A>G	TNXB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593448	NM_001365276.2(TNXB):c.10997_10998del (p.Val3666fs)	TNXB	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 10 · 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
TNXB	Supportive	Autosomal dominant	familial vesicoureteral reflux	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNXB	Orphanet:230839	Classical-like Ehlers-Danlos syndrome type 1
TNXB	Orphanet:289365	Familial vesicoureteral reflux
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
CYP21A2	Orphanet:315306	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
CYP21A2	Orphanet:315311	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

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
TNXB	HGNC:11976	ENSG00000168477	P22105	Tenascin-X	gencc,clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
CYP21A2	HGNC:2600	ENSG00000231852	P08686	Steroid 21-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNXB	Tenascin-X	Appears to mediate interactions between cells and the extracellular matrix.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
CYP21A2	Steroid 21-hydroxylase	A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNXB	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
CYP21A2	Enzyme (other)	yes	1.14.14.16	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_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
right adrenal gland	2
right adrenal gland cortex	2
apex of heart	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNXB	134	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CYP21A2	130	tissue_specific	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC2	4,135
TNXB	1,335
CYP21A2	28

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNXB	P22105	3
TSC2	P49815	2
CYP21A2	P08686	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective CYP21A2 causes AH3	1	1903.3×	0.007	CYP21A2
Inhibition of TSC complex formation by AKT (PKB)	1	761.3×	0.009	TSC2
Mineralocorticoid biosynthesis	1	475.8×	0.009	CYP21A2
Glucocorticoid biosynthesis	1	292.8×	0.010	CYP21A2
AKT phosphorylates targets in the cytosol	1	271.9×	0.010	TSC2
Constitutive Signaling by AKT1 E17K in Cancer	1	141.0×	0.012	TSC2
Endogenous sterols	1	131.3×	0.012	CYP21A2
Energy dependent regulation of mTOR by LKB1-AMPK	1	131.3×	0.012	TSC2
TBC/RABGAPs	1	86.5×	0.017	TSC2
ECM proteoglycans	1	50.1×	0.026	TNXB
TP53 Regulates Metabolic Genes	1	43.3×	0.027	TSC2
Macroautophagy	1	38.5×	0.028	TSC2
Extracellular matrix organization	1	21.0×	0.047	TNXB

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
positive regulation of cell fate determination	1	5617.3×	0.008	TNXB
mineralocorticoid biosynthetic process	1	1404.3×	0.011	CYP21A2
positive regulation of collagen fibril organization	1	1404.3×	0.011	TNXB
cortisol biosynthetic process	1	702.2×	0.011	CYP21A2
regulation of insulin receptor signaling pathway	1	561.7×	0.011	TSC2
glucocorticoid biosynthetic process	1	510.7×	0.011	CYP21A2
elastic fiber assembly	1	510.7×	0.011	TNXB
negative regulation of mitophagy	1	510.7×	0.011	TSC2
anoikis	1	432.1×	0.012	TSC2
positive regulation of vascular endothelial growth factor signaling pathway	1	374.5×	0.012	TNXB
collagen metabolic process	1	351.1×	0.012	TNXB
regulation of JNK cascade	1	295.6×	0.012	TNXB
sterol metabolic process	1	280.9×	0.012	CYP21A2
positive chemotaxis	1	267.5×	0.012	TSC2
steroid biosynthetic process	1	200.6×	0.015	CYP21A2
negative regulation of TOR signaling	1	187.2×	0.015	TSC2
positive regulation of macroautophagy	1	175.5×	0.015	TSC2
regulation of endocytosis	1	160.5×	0.016	TSC2
triglyceride metabolic process	1	147.8×	0.016	TNXB
regulation of cell differentiation	1	144.0×	0.016	TNXB
negative regulation of insulin receptor signaling pathway	1	124.8×	0.017	TSC2
negative regulation of Wnt signaling pathway	1	114.6×	0.017	TSC2
steroid metabolic process	1	112.3×	0.017	CYP21A2
negative regulation of TORC1 signaling	1	108.0×	0.017	TSC2
positive regulation of epithelial to mesenchymal transition	1	106.0×	0.017	TNXB
regulation of cell adhesion	1	102.1×	0.017	TNXB
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	87.8×	0.019	TSC2
collagen fibril organization	1	74.9×	0.022	TNXB
fatty acid metabolic process	1	64.6×	0.024	TNXB
cellular response to starvation	1	64.6×	0.024	TSC2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYP21A2	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP21A2	4	4
TNXB	0	0
TSC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP21A2	15	Binding:10, ADMET:5
TSC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP21A2	1.14.14.16	steroid 21-monooxygenase

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

4 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.

Compound	Max phase	Cohort target (bioactivity)
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP21A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TNXB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TSC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNXB	0	—
TSC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.