Congenital anomalies of kidney and urinary tract 1

Summary

Congenital anomalies of kidney and urinary tract 1 (MONDO:0012561) is a disease caused by DSTYK (GenCC Definitive), with 6 cohort genes and 2 clinical trials. Top therapeutic interventions include cefixime, nitrofurantoin, and sulfamethoxazole.

At a glance

• Causal gene: DSTYK (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 36
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital anomalies of kidney and urinary tract 1
Mondo ID	MONDO:0012561
MeSH	C563661
OMIM	610805
DOID	DOID:0080206
UMLS	C1835826
MedGen	322763
GARD	0024873
Is cancer (heuristic)	no

Also known as: CAKUT1 · congenital anomalies of kidney and urinary tract 1 · congenital anomaly of kidney and urinary tract caused by mutation in DSTYK · DSTYK congenital anomaly of kidney and urinary tract · renal hypodysplasia, nonsyndromic, 1

Data availability: 36 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › congenital anomaly of kidney and urinary tract › congenital anomalies of kidney and urinary tract 1

Related subtypes (2): congenital anomalies of kidney and urinary tract 2, congenital anomalies of kidney and urinary tract 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

36 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 10 likely pathogenic, 7 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506422	NM_016292.3(TRAP1):c.1915C>T (p.Gln639Ter)	DNASE1	Pathogenic	no assertion criteria provided
60685	NM_015375.3(DSTYK):c.24G>A (p.Trp8Ter)	DSTYK	Pathogenic	no assertion criteria provided
2672065	NM_001407.3(CELSR3):c.3142C>T (p.Arg1048Trp)	CELSR3	Likely pathogenic	no assertion criteria provided
2672066	NM_001407.3(CELSR3):c.3100G>C (p.Glu1034Gln)	CELSR3	Likely pathogenic	no assertion criteria provided
1333318	NM_015375.3(DSTYK):c.1053dup (p.Gln352fs)	DSTYK	Likely pathogenic	criteria provided, single submitter
3065572	NM_015375.3(DSTYK):c.1477G>T (p.Gly493Ter)	DSTYK	Likely pathogenic	criteria provided, single submitter
3235733	NM_015375.3(DSTYK):c.1394A>G (p.Gln465Arg)	DSTYK	Likely pathogenic	criteria provided, single submitter
3899994	NM_015375.3(DSTYK):c.889del (p.Glu297fs)	DSTYK	Likely pathogenic	no assertion criteria provided
3602562	NM_000278.5(PAX2):c.763C>T (p.Gln255Ter)	PAX2	Likely pathogenic	criteria provided, single submitter
3602563	NM_000278.5(PAX2):c.206T>C (p.Leu69Pro)	PAX2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3602564	NM_000278.5(PAX2):c.983G>T (p.Gly328Val)	PAX2	Likely pathogenic	criteria provided, single submitter
3602569	NM_000278.5(PAX2):c.617-1G>T	PAX2	Likely pathogenic	criteria provided, single submitter
1031910	NM_015375.3(DSTYK):c.1384C>T (p.Arg462Ter)	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224356	NM_015375.3(DSTYK):c.1775G>A (p.Arg592Gln)	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224358	NM_015375.3(DSTYK):c.53C>T (p.Pro18Leu)	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224360	NM_015375.3(DSTYK):c.1819-3C>T	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60684	NM_015375.3(DSTYK):c.654+1G>A	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60687	NM_015375.3(DSTYK):c.86G>A (p.Arg29Gln)	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873	NM_006953.4(UPK3A):c.818C>T (p.Pro273Leu)	UPK3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298379	NM_015375.3(DSTYK):c.1060C>G (p.Arg354Gly)	DSTYK	Uncertain significance	criteria provided, single submitter
1933941	NM_015375.3(DSTYK):c.1877G>A (p.Arg626Gln)	DSTYK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1952039	NM_015375.3(DSTYK):c.1979G>A (p.Arg660Gln)	DSTYK	Uncertain significance	criteria provided, single submitter
224357	NM_015375.3(DSTYK):c.358G>A (p.Asp120Asn)	DSTYK	Uncertain significance	criteria provided, single submitter
224359	NM_015375.3(DSTYK):c.2368C>T (p.Arg790Cys)	DSTYK	Uncertain significance	criteria provided, single submitter
224361	NM_015375.3(DSTYK):c.1253A>G (p.Asp418Gly)	DSTYK	Uncertain significance	criteria provided, single submitter
2371404	NM_015375.3(DSTYK):c.95G>A (p.Gly32Asp)	DSTYK	Uncertain significance	criteria provided, multiple submitters, no conflicts
3578158	NM_015375.3(DSTYK):c.1317G>C (p.Glu439Asp)	DSTYK	Uncertain significance	criteria provided, single submitter
3578160	NM_015375.3(DSTYK):c.55G>A (p.Gly19Ser)	DSTYK	Uncertain significance	criteria provided, single submitter
3900618	NM_015375.3(DSTYK):c.1819-18T>A	DSTYK	Uncertain significance	criteria provided, single submitter
828135	NM_015375.3(DSTYK):c.2605G>T (p.Ala869Ser)	DSTYK	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
DSTYK	Definitive	Autosomal dominant	congenital anomalies of kidney and urinary tract 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSTYK	Orphanet:101003	Autosomal recessive spastic paraplegia type 23
DSTYK	Orphanet:93100	Renal agenesis, unilateral
UPK3A	Orphanet:93100	Renal agenesis, unilateral
DNASE1	Orphanet:300345	Autosomal systemic lupus erythematosus
DNASE1	Orphanet:536	Systemic lupus erythematosus
PAX2	Orphanet:1475	Renal coloboma syndrome
PAX2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
PAX2	Orphanet:97362	Renal hypoplasia, bilateral

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSTYK	HGNC:29043	ENSG00000133059	Q6XUX3	Dual serine/threonine and tyrosine protein kinase	gencc,clinvar
UPK3A	HGNC:12580	ENSG00000100373	O75631	Uroplakin-3a	clinvar
SRGAP1	HGNC:17382	ENSG00000196935	Q7Z6B7	SLIT-ROBO Rho GTPase-activating protein 1	clinvar
DNASE1	HGNC:2956	ENSG00000213918	P24855	Deoxyribonuclease-1	clinvar
CELSR3	HGNC:3230	ENSG00000008300	Q9NYQ7	Cadherin EGF LAG seven-pass G-type receptor 3	clinvar
PAX2	HGNC:8616	ENSG00000075891	Q02962	Paired box protein Pax-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSTYK	Dual serine/threonine and tyrosine protein kinase	Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation.
UPK3A	Uroplakin-3a	Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.
SRGAP1	SLIT-ROBO Rho GTPase-activating protein 1	GTPase-activating protein for RhoA and Cdc42 small GTPases.
DNASE1	Deoxyribonuclease-1	Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs.
CELSR3	Cadherin EGF LAG seven-pass G-type receptor 3	Receptor that may have an important role in cell/cell signaling during nervous system formation.
PAX2	Paired box protein Pax-2	Transcription factor that may have a role in kidney cell differentiation.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	14.0×	0.417
Kinase	1	4.6×	0.451
GPCR	1	4.0×	0.451
Scaffold/PPI	1	2.9×	0.451
Transcription factor	1	1.4×	0.647
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSTYK	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
UPK3A	Other/Unknown	no		Uroplakin-3a, Uroplakin-3
SRGAP1	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
DNASE1	Phosphatase	yes	3.1.21.1	Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
CELSR3	GPCR	yes		GPS, EGF, GPCR_2_secretin-like
PAX2	Transcription factor	no		Paired_dom, Homeodomain-like_sf, Pax2_C

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
medial globus pallidus	2
cortical plate	2
lateral nuclear group of thalamus	1
superior vestibular nucleus	1
gastrocnemius	1
mucosa of urinary bladder	1
muscle of leg	1
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1
small intestine Peyer’s patch	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adult mammalian kidney	1
metanephros cortex	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSTYK	287	ubiquitous	marker	lateral nuclear group of thalamus, medial globus pallidus, superior vestibular nucleus
UPK3A	126	broad	marker	gastrocnemius, mucosa of urinary bladder, muscle of leg
SRGAP1	236	ubiquitous	marker	buccal mucosa cell, cortical plate, medial globus pallidus
DNASE1	226	ubiquitous	marker	duodenum, jejunal mucosa, small intestine Peyer’s patch
CELSR3	209	broad	yes	right hemisphere of cerebellum, cortical plate, cerebellar hemisphere
PAX2	92	broad	marker	metanephros cortex, renal medulla, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX2	2,208
DSTYK	1,487
CELSR3	1,213
SRGAP1	1,122
DNASE1	1,051
UPK3A	508

Structural data

PDB: 1 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNASE1	P24855	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSTYK	Q6XUX3	81.02
UPK3A	O75631	78.77
SRGAP1	Q7Z6B7	73.49
PAX2	Q02962	61.52
CELSR3	Q9NYQ7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 6 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inactivation of CDC42 and RAC1	1	713.8×	0.011	SRGAP1
Formation of intermediate mesoderm	1	713.8×	0.011	PAX2
Nephron development	1	439.2×	0.012	PAX2
Formation of the nephric duct	1	317.2×	0.013	PAX2
Formation of the ureteric bud	1	248.3×	0.013	PAX2
Signaling by ROBO receptors	1	62.1×	0.043	SRGAP1
RHOA GTPase cycle	1	37.3×	0.053	SRGAP1
CDC42 GTPase cycle	1	36.1×	0.053	SRGAP1
RAC1 GTPase cycle	1	30.5×	0.053	SRGAP1
RHO GTPase cycle	1	30.1×	0.053	SRGAP1
Axon guidance	1	22.6×	0.061	SRGAP1
Nervous system development	1	21.5×	0.061	SRGAP1
Signaling by Rho GTPases	1	17.1×	0.067	SRGAP1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.067	SRGAP1
Developmental Biology	1	7.2×	0.142	SRGAP1
Signal Transduction	1	5.1×	0.187	SRGAP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
optic chiasma development	1	2808.7×	0.005	PAX2
positive regulation of optic nerve formation	1	2808.7×	0.005	PAX2
optic cup morphogenesis involved in camera-type eye development	1	1404.3×	0.005	PAX2
optic nerve structural organization	1	1404.3×	0.005	PAX2
regulation of metanephros size	1	1404.3×	0.005	PAX2
pronephric field specification	1	1404.3×	0.005	PAX2
regulation of neutrophil mediated cytotoxicity	1	1404.3×	0.005	DNASE1
obsolete negative regulation of mesenchymal cell apoptotic process involved in metanephric nephron morphogenesis	1	1404.3×	0.005	PAX2
obsolete negative regulation of apoptotic process involved in metanephric collecting duct development	1	1404.3×	0.005	PAX2
obsolete negative regulation of apoptotic process involved in metanephric nephron tubule development	1	1404.3×	0.005	PAX2
positive regulation of metanephric DCT cell differentiation	1	1404.3×	0.005	PAX2
axonogenesis	2	53.5×	0.005	CELSR3, PAX2
dopaminergic neuron axon guidance	1	936.2×	0.005	CELSR3
serotonergic neuron axon guidance	1	936.2×	0.005	CELSR3
nephric duct formation	1	936.2×	0.005	PAX2
positive regulation of metanephric glomerulus development	1	936.2×	0.005	PAX2
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	936.2×	0.005	PAX2
regulation of acute inflammatory response	1	702.2×	0.005	DNASE1
urea transport	1	702.2×	0.005	UPK3A
ureter maturation	1	702.2×	0.005	PAX2
urinary bladder development	1	702.2×	0.005	UPK3A
metanephric distal convoluted tubule development	1	702.2×	0.005	PAX2
optic nerve morphogenesis	1	561.7×	0.005	PAX2
vestibulocochlear nerve formation	1	561.7×	0.005	PAX2
positive regulation of kinase activity	1	561.7×	0.005	DSTYK
metanephric mesenchymal cell differentiation	1	561.7×	0.005	PAX2
metanephric epithelium development	1	561.7×	0.005	PAX2
metanephric nephron tubule formation	1	561.7×	0.005	PAX2
regulation of metanephric nephron tubule epithelial cell differentiation	1	561.7×	0.005	PAX2
positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	468.1×	0.006	PAX2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
DSTYK	FEDRATINIB
DNASE1	GENTIAN VIOLET

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSTYK	15	4
DNASE1	1	4
UPK3A	0	0
SRGAP1	0	0
CELSR3	0	0
PAX2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	DSTYK
NERATINIB	4	DSTYK
DABRAFENIB	4	DSTYK
BOSUTINIB	4	DSTYK
SUNITINIB	4	DSTYK
CRIZOTINIB	4	DSTYK
MIDOSTAURIN	4	DSTYK
GENTIAN VIOLET	4	DNASE1
ALVOCIDIB	3	DSTYK
LESTAURTINIB	3	DSTYK
FORETINIB	2	DSTYK
SU-014813	2	DSTYK
DEFOSBARASERTIB	2	DSTYK
RG-547	2	DSTYK
KW-2449	1	DSTYK
AST-487	1	DSTYK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DSTYK	90	Binding:90
DNASE1	4	Binding:4
PAX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNASE1	3.1.21.1	deoxyribonuclease I

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

16 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)
FEDRATINIB	4	DSTYK
NERATINIB	4	DSTYK
DABRAFENIB	4	DSTYK
BOSUTINIB	4	DSTYK
SUNITINIB	4	DSTYK
CRIZOTINIB	4	DSTYK
MIDOSTAURIN	4	DSTYK
GENTIAN VIOLET	4	DNASE1
ALVOCIDIB	3	DSTYK
LESTAURTINIB	3	DSTYK
FORETINIB	2	DSTYK
SU-014813	2	DSTYK
DEFOSBARASERTIB	2	DSTYK
RG-547	2	DSTYK
KW-2449	1	DSTYK
AST-487	1	DSTYK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	DSTYK, DNASE1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CELSR3
E	Difficult family or no structure, no drug	3	UPK3A, SRGAP1, PAX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UPK3A	0	—
SRGAP1	0	—
CELSR3	0	—
PAX2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02021006	PHASE3	UNKNOWN	Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
NCT00925379	Not specified	COMPLETED	Renal HYPODYSPLASIA : Genetic and Familial Assessment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CEFIXIME	4	1
NITROFURANTOIN	4	1
SULFAMETHOXAZOLE	4	1
TRIMETHOPRIM	4	1