Vesicoureteral reflux 2

Summary

Vesicoureteral reflux 2 (MONDO:0012573) is a disease caused by ROBO2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ROBO2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 306

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vesicoureteral reflux 2
Mondo ID	MONDO:0012573
MeSH	C567053
OMIM	610878
UMLS	C1970483
MedGen	370270
GARD	0018419
Is cancer (heuristic)	no

Also known as: ROBO2 vesicoureteral reflux (disease) · vesicoureteral reflux (disease) caused by mutation in ROBO2 · vesicoureteral reflux 2 · vesicoureteral reflux type 2 · VUR2

Data availability: 306 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial vesicoureteral reflux › vesicoureteral reflux 2

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

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

306 retrieved; paginated sample, class counts are floors:

193 uncertain significance, 58 benign, 20 conflicting classifications of pathogenicity, 18 benign/likely benign, 17 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1128534	NM_001395656.1(ROBO2):c.928G>A (p.Val310Ile)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2170255	NM_001395656.1(ROBO2):c.3241C>G (p.Pro1081Ala)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2171357	NM_001395656.1(ROBO2):c.1964C>T (p.Thr655Met)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224345	NM_001395656.1(ROBO2):c.2443C>T (p.Arg815Trp)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224346	NM_001395656.1(ROBO2):c.335C>T (p.Ala112Val)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224347	NM_001128929.3(ROBO2):c.97G>T (p.Gly33Ter)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2636818	NM_001395656.1(ROBO2):c.1448G>A (p.Arg483Gln)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3434692	NM_001395656.1(ROBO2):c.3866C>T (p.Pro1289Leu)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346688	NM_001395656.1(ROBO2):c.1706G>C (p.Ser569Thr)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346706	NM_001395656.1(ROBO2):c.3484C>T (p.Arg1162Trp)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346711	NM_001395656.1(ROBO2):c.3869G>T (p.Arg1290Leu)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346716	NM_001395656.1(ROBO2):c.4420+5G>C	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3589527	NM_001395656.1(ROBO2):c.123C>T (p.Ile41=)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3589590	NM_001395656.1(ROBO2):c.3052G>A (p.Asp1018Asn)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3589612	NM_001395656.1(ROBO2):c.3567-13A>C	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
809509	NM_001395656.1(ROBO2):c.3245C>G (p.Pro1082Arg)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899790	NM_001395656.1(ROBO2):c.3896G>T (p.Arg1299Leu)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902553	NM_001395656.1(ROBO2):c.2407G>A (p.Val803Ile)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903407	NM_001395656.1(ROBO2):c.3328C>T (p.Pro1110Ser)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903408	NM_001395656.1(ROBO2):c.3565T>G (p.Trp1189Gly)	ROBO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3589562	NM_001395656.1(ROBO2):c.2018G>A (p.Arg673Gln)	LOC126806727	Uncertain significance	criteria provided, single submitter
3589564	NM_001395656.1(ROBO2):c.2056T>A (p.Ser686Thr)	LOC126806727	Uncertain significance	criteria provided, single submitter
3589566	NM_001395656.1(ROBO2):c.2099G>A (p.Ser700Asn)	LOC126806727	Uncertain significance	criteria provided, single submitter
3589567	NM_001395656.1(ROBO2):c.2150G>A (p.Arg717Gln)	LOC126806727	Uncertain significance	criteria provided, multiple submitters, no conflicts
900884	NM_001395656.1(ROBO2):c.2024T>C (p.Met675Thr)	LOC126806727	Uncertain significance	criteria provided, single submitter
900887	NM_001395656.1(ROBO2):c.2200C>T (p.Arg734Cys)	LOC126806727	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033555	NM_001395656.1(ROBO2):c.3926G>A (p.Arg1309Gln)	ROBO2	Uncertain significance	criteria provided, single submitter
1050325	NM_001395656.1(ROBO2):c.2578G>C (p.Val860Leu)	ROBO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299324	NM_001395656.1(ROBO2):c.1670G>A (p.Ser557Asn)	ROBO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1303319	NM_001395656.1(ROBO2):c.371C>T (p.Ala124Val)	ROBO2	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
ROBO2	Strong	Autosomal dominant	vesicoureteral reflux 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROBO2	Orphanet:289365	Familial vesicoureteral reflux

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
ROBO2	HGNC:10250	ENSG00000185008	Q9HCK4	Roundabout homolog 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROBO2	Roundabout homolog 2	Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neu…

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)
ROBO2	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
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROBO2	192	broad	marker	ganglionic eminence, cortical plate, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ROBO2	2,181

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ROBO2	Q9HCK4	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Regulation of cortical dendrite branching	1	2284.0×	0.003	ROBO2
ROBO receptors bind AKAP5	1	1268.9×	0.003	ROBO2
Regulation of commissural axon pathfinding by SLIT and ROBO	1	951.7×	0.003	ROBO2
Kidney development	1	815.7×	0.003	ROBO2
Formation of the ureteric bud	1	496.5×	0.004	ROBO2
Signaling by ROBO receptors	1	124.1×	0.013	ROBO2
Regulation of expression of SLITs and ROBOs	1	69.2×	0.021	ROBO2
Axon guidance	1	45.1×	0.026	ROBO2
Nervous system development	1	42.9×	0.026	ROBO2
Developmental Biology	1	14.5×	0.069	ROBO2

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
olfactory bulb interneuron development	1	5617.3×	0.002	ROBO2
negative regulation of negative chemotaxis	1	5617.3×	0.002	ROBO2
apoptotic process involved in luteolysis	1	4213.0×	0.002	ROBO2
axon midline choice point recognition	1	3370.4×	0.002	ROBO2
negative regulation of synapse assembly	1	2407.4×	0.002	ROBO2
heart induction	1	2106.5×	0.002	ROBO2
endocardial cushion formation	1	1404.3×	0.002	ROBO2
pulmonary valve morphogenesis	1	936.2×	0.003	ROBO2
retinal ganglion cell axon guidance	1	766.0×	0.003	ROBO2
outflow tract septum morphogenesis	1	648.1×	0.003	ROBO2
positive regulation of axonogenesis	1	581.1×	0.003	ROBO2
aorta development	1	561.7×	0.003	ROBO2
metanephros development	1	510.7×	0.003	ROBO2
ureteric bud development	1	455.5×	0.003	ROBO2
aortic valve morphogenesis	1	432.1×	0.003	ROBO2
ventricular septum morphogenesis	1	432.1×	0.003	ROBO2
cellular response to hormone stimulus	1	383.0×	0.004	ROBO2
positive regulation of Notch signaling pathway	1	351.1×	0.004	ROBO2
homophilic cell-cell adhesion	1	140.4×	0.009	ROBO2
chemotaxis	1	135.9×	0.009	ROBO2
central nervous system development	1	115.4×	0.010	ROBO2
cell-cell adhesion	1	101.5×	0.011	ROBO2
axon guidance	1	90.6×	0.012	ROBO2
brain development	1	79.5×	0.013	ROBO2

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
ROBO2	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	1	ROBO2
D	Druggable family + AlphaFold only, no drug	0
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)
ROBO2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.