Congenital anomaly of kidney and urinary tract

Summary

Congenital anomaly of kidney and urinary tract (MONDO:0019719) is a disease caused by variants in LIFR, SHROOM4, and ZMYM2, with 75 cohort genes (1 GWAS associations across 4 studies) and 4 clinical trials. The dominant Reactome pathway is Formation of the ureteric bud (7 cohort genes).

At a glance

• Causal genes: LIFR (GenCC Strong), SHROOM4 (GenCC Strong), ZMYM2 (GenCC Strong)
• Cohort genes: 75
• GWAS associations: 1
• ClinVar variants: 176
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital anomaly of kidney and urinary tract
Mondo ID	MONDO:0019719
MeSH	C566906
OMIM	610805
Orphanet	93545
DOID	DOID:0080205
UMLS	C1968949
MedGen	369894
GARD	0019216
Is cancer (heuristic)	no

Also known as: CAKUT · congenital anomalies of kidney and urinary tract · congenital anomaly of kidney and urinary tract · renal or urinary tract malformation

Data availability: 176 ClinVar variants · 1 GWAS association (4 studies) · 19 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

Subtypes (3): congenital anomalies of kidney and urinary tract 1, congenital anomalies of kidney and urinary tract 2, congenital anomalies of kidney and urinary tract 3

Genetics & variants

GWAS landscape

1 GWAS associations across 4 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs186637459	9e-09	NUDT12 - NIHCOLE	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90482460	Verma A	2024	488	450,295	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436763	Zhou W	2018	339	406,730	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90436420	Zhou W	2018	213	397,602	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651455	Liu TY	2025	187	202,534	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs186637459	5	103947068	A>T	0.05	intergenic_variant	NUDT12 - NIHCOLE	9e-09	Tier 4: intronic/intergenic

ClinVar germline variants

176 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 34 conflicting classifications of pathogenicity, 25 likely pathogenic, 17 pathogenic, 17 pathogenic/likely pathogenic, 5 benign/likely benign, 2 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
988100	NM_000789.4(ACE):c.1709+5G>C	ACE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29585	NM_001614.5(ACTG1):c.464C>T (p.Ser155Phe)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1307836	NM_015557.3(CHD5):c.4852C>T (p.Arg1618Ter)	CHD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219099	NM_015047.3(EMC1):c.2619_2622del (p.Pro874fs)	EMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235484	NM_025074.7(FRAS1):c.7551T>A (p.Tyr2517Ter)	FRAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635698	NM_000458.4(HNF1B):c.443C>T (p.Ser148Leu)	HNF1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344620	NM_021828.5(HPSE2):c.1099-2A>G	HPSE2	Pathogenic	no assertion criteria provided
89	NM_021828.5(HPSE2):c.457C>T (p.Arg153Ter)	HPSE2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
369648	NM_001127671.2(LIFR):c.1273_1276del (p.Val425fs)	LIFR	Pathogenic	criteria provided, single submitter
219378	NM_017617.5(NOTCH1):c.1649dup (p.Tyr550Ter)	NOTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1344621	NM_001128178.3(NPHP1):c.1636del (p.Ser546fs)	NPHP1	Pathogenic	no assertion criteria provided
598394	NM_153240.5(NPHP3):c.406del (p.Thr136fs)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548653	NM_003489.4(NRIP1):c.279del (p.Asp92_Trp93insTer)	NRIP1	Pathogenic	no assertion criteria provided
156297	NM_000278.5(PAX2):c.76dup (p.Val26fs)	PAX2	Pathogenic	criteria provided, multiple submitters, no conflicts
41442	NM_002834.5(PTPN11):c.178G>T (p.Gly60Cys)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1077087	NM_002941.4(ROBO1):c.4156G>T (p.Gly1386Ter)	ROBO1	Pathogenic	criteria provided, single submitter
1077089	NM_002941.4(ROBO1):c.687C>G (p.Tyr229Ter)	ROBO1	Pathogenic	criteria provided, single submitter
1077090	NM_002941.4(ROBO1):c.2758C>T (p.Arg920Ter)	ROBO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321867	NM_002941.4(ROBO1):c.2630_2631del (p.Pro877fs)	ROBO1	Pathogenic	criteria provided, single submitter
996027	NM_002941.4(ROBO1):c.1198C>T (p.Gln400Ter)	ROBO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996034	NM_002941.4(ROBO1):c.1342+1G>A	ROBO1	Pathogenic	criteria provided, single submitter
996098	NM_002941.4(ROBO1):c.2882+1G>T	ROBO1	Pathogenic	criteria provided, single submitter
684623	NM_004787.4(SLIT2):c.292G>A (p.Ala98Thr)	SLIT2	Pathogenic	no assertion criteria provided
684624	NM_004787.4(SLIT2):c.2712A>T (p.Lys904Asn)	SLIT2	Pathogenic	no assertion criteria provided
208527	NM_001080508.3(TBX18):c.1010del (p.Gly337fs)	TBX18	Pathogenic/Likely pathogenic	no assertion criteria provided
5578	NM_014112.5(TRPS1):c.2795C>T (p.Ala932Val)	TRPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1264312	NM_197968.4(ZMYM2):c.1618C>T (p.Arg540Ter)	ZMYM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1264313	NM_197968.4(ZMYM2):c.1607del (p.Cys536fs)	ZMYM2	Pathogenic/Likely pathogenic	no assertion criteria provided
1264314	NM_197968.4(ZMYM2):c.766_767dup (p.Val256_Gly257insTer)	ZMYM2	Pathogenic/Likely pathogenic	no assertion criteria provided
1264315	NM_197968.4(ZMYM2):c.2434_2437del (p.Lys812fs)	ZMYM2	Pathogenic/Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 67 · Orphanet: 151 · 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
LIFR	Strong	Autosomal dominant	congenital anomaly of kidney and urinary tract	6
SHROOM4	Strong	X-linked	congenital anomaly of kidney and urinary tract	5
TBC1D1	Strong	Autosomal dominant	non-syndromic renal or urinary tract malformation	2
ZMYM2	Strong	Autosomal dominant	congenital anomaly of kidney and urinary tract	6
BCORL1	Moderate	X-linked	congenital anomaly of kidney and urinary tract	8
BMP7	Moderate	Autosomal dominant	multiple congenital anomalies/dysmorphic syndrome	5
SLIT2	Moderate	Autosomal dominant	congenital anomaly of kidney and urinary tract
SLIT3	Moderate	Autosomal dominant	congenital anomaly of kidney and urinary tract	2
SRGAP1	Moderate	Autosomal dominant	congenital anomaly of kidney and urinary tract	2
TSHZ3	Moderate	Autosomal dominant	congenital anomaly of kidney and urinary tract	3
ARHGEF6	Limited	X-linked	congenital anomaly of kidney and urinary tract	8
CHD1L	Limited	Unknown	congenital anomaly of kidney and urinary tract
DLG5	Limited	Autosomal recessive	congenital anomaly of kidney and urinary tract	6
SIX2	Limited	Autosomal dominant	congenital anomaly of kidney and urinary tract
TBC1D31	Limited	Autosomal recessive	congenital anomaly of kidney and urinary tract
TBX6	Limited	Autosomal dominant	congenital anomaly of kidney and urinary tract	6
VWA2	Limited	Autosomal recessive	congenital anomaly of kidney and urinary tract
UPK3A	Disputed Evidence	Autosomal dominant	congenital anomaly of kidney and urinary tract	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIX2	Orphanet:488437	SIX2-related frontonasal dysplasia
ZMYM2	Orphanet:528084	Non-specific syndromic intellectual disability
LIFR	Orphanet:3206	Stüve-Wiedemann syndrome
TBX6	Orphanet:1797	Autosomal dominant spondylocostal dysostosis
TBX6	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
UPK3A	Orphanet:93100	Renal agenesis, unilateral
BCORL1	Orphanet:528084	Non-specific syndromic intellectual disability
SHROOM4	Orphanet:85288	X-linked intellectual disability, Stocco Dos Santos type
ARHGEF6	Orphanet:777	X-linked non-syndromic intellectual disability
ROBO1	Orphanet:95496	Pituitary stalk interruption syndrome
ROBO2	Orphanet:289365	Familial vesicoureteral reflux
SALL1	Orphanet:857	Townes-Brocks syndrome
SOX5	Orphanet:313884	12p12.1 microdeletion syndrome
SOX5	Orphanet:313892	Developmental and speech delay due to SOX5 deficiency
SOX5	Orphanet:626	Large/giant congenital melanocytic nevus
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
TRIO	Orphanet:476126	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
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
CACNA1D	Orphanet:324321	Sinoatrial node dysfunction and deafness
CACNA1D	Orphanet:369929	Primary hyperaldosteronism-seizures-neurological abnormalities syndrome
SHANK3	Orphanet:662169	Phelan-McDermid syndrome due to 22q13.3 deletion
SHANK3	Orphanet:662172	Phelan-McDermid syndrome due to SHANK3 mutation
ACTG1	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTG1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:98942	Coloboma of choroid and retina
ACTG1	Orphanet:98944	Coloboma of iris
GATA5	Orphanet:3303	Tetralogy of Fallot
GATA5	Orphanet:334	Hereditary atrial fibrillation
GATA5	Orphanet:402075	Familial bicuspid aortic valve
SALL4	Orphanet:2307	IVIC syndrome

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMP7	HGNC:1074	ENSG00000101144	P18075	Bone morphogenetic protein 7	gencc,clinvar
SIX2	HGNC:10888	ENSG00000170577	Q9NPC8	Homeobox protein SIX2	gencc,clinvar
SLIT2	HGNC:11086	ENSG00000145147	O94813	Slit homolog 2 protein	gencc,clinvar
SLIT3	HGNC:11087	ENSG00000184347	O75094	Slit homolog 3 protein	gencc,clinvar
TBC1D1	HGNC:11578	ENSG00000065882	Q86TI0	TBC1 domain family member 1	gencc,clinvar
ZMYM2	HGNC:12989	ENSG00000121741	Q9UBW7	Zinc finger MYM-type protein 2	gencc,clinvar
SRGAP1	HGNC:17382	ENSG00000196935	Q7Z6B7	SLIT-ROBO Rho GTPase-activating protein 1	gencc,clinvar
CHD1L	HGNC:1916	ENSG00000131778	Q86WJ1	ATP-dependent chromatin remodeler CHD1L	gencc,clinvar
TSHZ3	HGNC:30700	ENSG00000121297	Q63HK5	Teashirt homolog 3	gencc,clinvar
LIFR	HGNC:6597	ENSG00000113594	P42702	Leukemia inhibitory factor receptor	gencc,clinvar
TBX6	HGNC:11605	ENSG00000149922	O95947	T-box transcription factor TBX6	gencc
UPK3A	HGNC:12580	ENSG00000100373	O75631	Uroplakin-3a	gencc
VWA2	HGNC:24709	ENSG00000165816	Q5GFL6	von Willebrand factor A domain-containing protein 2	gencc
BCORL1	HGNC:25657	ENSG00000085185	Q5H9F3	BCL-6 corepressor-like protein 1	gencc
DLG5	HGNC:2904	ENSG00000151208	Q8TDM6	Disks large homolog 5	gencc
SHROOM4	HGNC:29215	ENSG00000158352	Q9ULL8	Protein Shroom4	gencc
TBC1D31	HGNC:30888	ENSG00000156787	Q96DN5	TBC1 domain family member 31	gencc
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	gencc
ROBO1	HGNC:10249	ENSG00000169855	Q9Y6N7	Roundabout homolog 1	clinvar
ROBO2	HGNC:10250	ENSG00000185008	Q9HCK4	Roundabout homolog 2	clinvar
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	clinvar
SOX5	HGNC:11201	ENSG00000134532	P35711	Transcription factor SOX-5	clinvar
TBX18	HGNC:11595	ENSG00000112837	O95935	T-box transcription factor TBX18	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
HSP90B2P	HGNC:12099	ENSG00000259706	Q58FF3	Putative endoplasmin-like protein	clinvar
TRIO	HGNC:12303	ENSG00000038382	O75962	Triple functional domain protein	clinvar
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
GET1	HGNC:12790	ENSG00000182093	O00258	Guided entry of tail-anchored proteins factor 1	clinvar
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	clinvar
SHANK3	HGNC:14294	ENSG00000251322	Q9BYB0	SH3 and multiple ankyrin repeat domains protein 3	clinvar
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	clinvar
GATA5	HGNC:15802	ENSG00000130700	Q9BWX5	Transcription factor GATA-5	clinvar
SALL4	HGNC:15924	ENSG00000101115	Q9UJQ4	Sal-like protein 4	clinvar
TRAP1	HGNC:16264	ENSG00000126602	Q12931	Heat shock protein 75 kDa, mitochondrial	clinvar
CHD5	HGNC:16816	ENSG00000116254	Q8TDI0	ATP-dependent chromatin remodeler CHD5	clinvar
CDON	HGNC:17104	ENSG00000064309	Q4KMG0	Cell adhesion molecule-related/down-regulated by oncogenes	clinvar
CDC5L	HGNC:1743	ENSG00000096401	Q99459	Cell division cycle 5-like protein	clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
HPSE2	HGNC:18374	ENSG00000172987	Q8WWQ2	Inactive heparanase-2	clinvar
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	clinvar
NPHP4	HGNC:19104	ENSG00000131697	O75161	Nephrocystin-4	clinvar
FRAS1	HGNC:19185	ENSG00000138759	Q86XX4	Extracellular matrix organizing protein FRAS1	clinvar
BICC1	HGNC:19351	ENSG00000122870	Q9H694	Protein bicaudal C homolog 1	clinvar
BCOR	HGNC:20893	ENSG00000183337	Q6W2J9	BCL-6 corepressor	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
MED13	HGNC:22474	ENSG00000108510	Q9UHV7	Mediator of RNA polymerase II transcription subunit 13	clinvar
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	clinvar
FREM1	HGNC:23399	ENSG00000164946	Q5H8C1	FRAS1-related extracellular matrix protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP7	Bone morphogenetic protein 7	Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis.
SIX2	Homeobox protein SIX2	Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach.
SLIT2	Slit homolog 2 protein	Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors.
SLIT3	Slit homolog 3 protein	May act as molecular guidance cue in cellular migration, and function may be mediated by interaction with roundabout homolog receptors.
TBC1D1	TBC1 domain family member 1	May act as a GTPase-activating protein for Rab family protein(s).
ZMYM2	Zinc finger MYM-type protein 2	Involved in the negative regulation of transcription.
SRGAP1	SLIT-ROBO Rho GTPase-activating protein 1	GTPase-activating protein for RhoA and Cdc42 small GTPases.
CHD1L	ATP-dependent chromatin remodeler CHD1L	ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage.
TSHZ3	Teashirt homolog 3	Transcriptional regulator involved in developmental processes.
LIFR	Leukemia inhibitory factor receptor	Signal-transducing molecule.
TBX6	T-box transcription factor TBX6	T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal.
UPK3A	Uroplakin-3a	Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.
BCORL1	BCL-6 corepressor-like protein 1	Transcriptional corepressor.
DLG5	Disks large homolog 5	Acts as a regulator of the Hippo signaling pathway.
SHROOM4	Protein Shroom4	Probable regulator of cytoskeletal architecture that plays an important role in development.
TBC1D31	TBC1 domain family member 31	Molecular adapter which is involved in cilium biogenesis.
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).
ROBO1	Roundabout homolog 1	Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuro…
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…
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
SOX5	Transcription factor SOX-5	Transcription factor involved in chondrocytes differentiation and cartilage formation.
TBX18	T-box transcription factor TBX18	Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
HSP90B2P	Putative endoplasmin-like protein	Putative molecular chaperone.
TRIO	Triple functional domain protein	Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases.
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
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…
GET1	Guided entry of tail-anchored proteins factor 1	Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER).
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
SHANK3	SH3 and multiple ankyrin repeat domains protein 3	Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance.
ACTG1	Actin, cytoplasmic 2	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
GATA5	Transcription factor GATA-5	Transcription factor required during cardiovascular development.
SALL4	Sal-like protein 4	Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.
TRAP1	Heat shock protein 75 kDa, mitochondrial	Chaperone that expresses an ATPase activity.
CHD5	ATP-dependent chromatin remodeler CHD5	ATP-dependent chromatin-remodeling factor that binds DNA through histones and regulates gene transcription.
CDON	Cell adhesion molecule-related/down-regulated by oncogenes	Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells.
CDC5L	Cell division cycle 5-like protein	DNA-binding protein involved in cell cycle control.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
HPSE2	Inactive heparanase-2	Binds heparin and heparan sulfate with high affinity, but lacks heparanase activity.
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
NPHP4	Nephrocystin-4	Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.
FRAS1	Extracellular matrix organizing protein FRAS1	Involved in extracellular matrix organization.
BICC1	Protein bicaudal C homolog 1	Putative RNA-binding protein.
BCOR	BCL-6 corepressor	Transcriptional corepressor.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
MED13	Mediator of RNA polymerase II transcription subunit 13	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.
FREM1	FRAS1-related extracellular matrix protein 1	Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
WDR62	WD repeat-containing protein 62	Required for cerebral cortical development.

Protein-family classification

Druggable: 9 · Difficult: 32 · Unknown: 34 · Druggable fraction: 0.12

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
Scaffold/PPI	14	3.2×	7e-04
Transcription factor	18	2.0×	0.012
Ion channel	2	3.0×	0.388
Antibody/Immunoglobulin	4	1.6×	0.511
Other/Unknown	34	0.8×	0.999
Protease	1	0.5×	0.999
Kinase	1	0.4×	0.999
Enzyme (other)	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP7	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SIX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SLIT2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
SLIT3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
TBC1D1	Other/Unknown	no		Rab-GAP-TBC_dom, PTB/PI_dom, PH-like_dom_sf
ZMYM2	Transcription factor	no		Znf_MYM, TRASH_dom, ZMYM2-like_C
SRGAP1	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
CHD1L	Other/Unknown	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
TSHZ3	Transcription factor	no		HD, Znf_C2H2_type, Teashirt_fam
LIFR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, FN3_dom, Ig-like_fold
TBX6	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
UPK3A	Other/Unknown	no		Uroplakin-3a, Uroplakin-3
VWA2	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, VWF_A
BCORL1	Scaffold/PPI	no		Ankyrin_rpt, PUFD, Ankyrin_rpt-contain_sf
DLG5	Scaffold/PPI	no		CARD, SH3_domain, PDZ
SHROOM4	Scaffold/PPI	no		PDZ, ASD2_dom, Shroom_fam
TBC1D31	Scaffold/PPI	no		Rab-GAP-TBC_dom, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom
ROBO1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ROBO2	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
SOX5	Transcription factor	no		HMG_box_dom, HMG_box_dom_sf, SOX/SOX-like_TF
TBX18	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
HSP90B2P	Other/Unknown	no		Hsp90_fam, Ribosomal_Su5_D2-typ_SF, HSP90_C
TRIO	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
GET1	Other/Unknown	no		Get1, Helix_hairpin_bin_sf
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
SHANK3	Scaffold/PPI	no		SH3_domain, PDZ, SAM
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
GATA5	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
SALL4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
TRAP1	Other/Unknown	no		Hsp90_fam, HATPase_dom, Ribosomal_Su5_D2-typ_SF
CHD5	Transcription factor	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
CDON	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
CDC5L	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, Myb_dom
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
HPSE2	Other/Unknown	no		Glyco_hydro_79, GH_hydrolase_sf
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
NPHP4	Other/Unknown	no		NPHP4, Ig_NPHP4_4th, Ig_NPHP4_3rd
FRAS1	Other/Unknown	no		EGF, VWF_dom, Calx_beta
BICC1	Other/Unknown	no		SAM, KH_dom, KH_dom_type_1
BCOR	Scaffold/PPI	no		Ankyrin_rpt, BCOR, PUFD
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
MED13	Other/Unknown	no		Med13_C, MID_MedPIWI, Mediator_complx_sub13
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
FREM1	Other/Unknown	no		C-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf

Expression context

Cohort genes with no expression data: 0.

70 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	12
buccal mucosa cell	8
cortical plate	8
calcaneal tendon	6
cerebellar hemisphere	5
primordial germ cell in gonad	5
right uterine tube	5
sural nerve	5
bronchial epithelial cell	5
gastrocnemius	4
oocyte	4
sperm	4
medial globus pallidus	4
ganglionic eminence	4
renal medulla	4
male germ line stem cell (sensu Vertebrata) in testis	4
cerebellar cortex	4
right hemisphere of cerebellum	4
olfactory segment of nasal mucosa	3
vena cava	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP7	243	broad	marker	pigmented layer of retina, ventricular zone, endometrium epithelium
SIX2	156	broad	marker	olfactory segment of nasal mucosa, gastrocnemius, parotid gland
SLIT2	274	ubiquitous	marker	lower lobe of lung, olfactory bulb, vena cava
SLIT3	254	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
TBC1D1	280	ubiquitous	marker	ventricular zone, body of uterus, muscle layer of sigmoid colon
ZMYM2	294	ubiquitous	marker	sperm, oocyte, secondary oocyte
SRGAP1	236	ubiquitous	marker	buccal mucosa cell, cortical plate, medial globus pallidus
CHD1L	233	ubiquitous	marker	primordial germ cell in gonad, C1 segment of cervical spinal cord, cerebellar hemisphere
TSHZ3	222	ubiquitous	marker	cortical plate, right ovary, left ovary
LIFR	269	ubiquitous	marker	medial globus pallidus, globus pallidus, lateral globus pallidus
TBX6	166	tissue_specific	marker	lower esophagus mucosa, buccal mucosa cell, diaphragm
UPK3A	126	broad	marker	gastrocnemius, mucosa of urinary bladder, muscle of leg
VWA2	122	broad	marker	thymus, right uterine tube, olfactory segment of nasal mucosa
BCORL1	250	ubiquitous	marker	cervix squamous epithelium, cardia of stomach, vena cava
DLG5	134	ubiquitous	marker	ventricular zone, left adrenal gland cortex, right adrenal gland cortex
SHROOM4	190	broad	marker	buccal mucosa cell, tendon of biceps brachii, left ventricle myocardium
TBC1D31	224	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus
ROBO1	287	ubiquitous	marker	ventricular zone, ganglionic eminence, tibia
ROBO2	192	broad	marker	ganglionic eminence, cortical plate, ventricular zone
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
SOX5	221	ubiquitous	marker	cortical plate, calcaneal tendon, synovial joint
TBX18	162	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
HSP90B2P	108	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, sural nerve
TRIO	279	ubiquitous	marker	sural nerve, cortical plate, stromal cell of endometrium
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GET1	292	ubiquitous	marker	bronchial epithelial cell, substantia nigra pars compacta, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EFTUD2	8,471
NOTCH1	7,411
GATA3	5,990
CDC5L	5,930
NOTCH2	5,266
TRAP1	5,216
JAG1	4,405
DHX8	4,332
TSC2	4,135
SHANK3	3,702

Intra-cohort edges

A	B	Sources
BCOR	BCORL1	string_interaction
BCOR	FRAS1	intact
BMP7	SMAD6	string_interaction
CACNA1D	SHANK3	intact
CDC5L	DHX8	biogrid_interaction
CDC5L	EFTUD2	string_interaction
CHD1L	HPSE2	string_interaction
DHX8	EFTUD2	string_interaction
DLG5	SHROOM4	intact
EFTUD2	MED12	biogrid_interaction
EFTUD2	MED13	biogrid_interaction
FAT4	SHANK3	intact
FOXC1	SALL1	intact
FRAS1	FREM1	string_interaction
FRAS1	FREM2	string_interaction
FRAS1	HPSE2	biogrid_interaction
FRAS1	VWA2	string_interaction
FREM1	FREM2	intact, string_interaction
FREM1	VWA2	string_interaction
FREM2	VWA2	string_interaction
GATA5	NKX2-5	string_interaction
JAG1	NOTCH1	intact, string_interaction
JAG1	NOTCH2	biogrid_interaction, string_interaction
JAG1	NOTCH4	string_interaction
MED12	MED13	biogrid_interaction, string_interaction
NKX2-5	SALL1	string_interaction
NKX2-5	SALL4	string_interaction
NKX2-5	TBX18	string_interaction
NKX2-5	TBX6	string_interaction
NOTCH1	NOTCH4	string_interaction
NPHP1	NPHP3	biogrid_interaction, string_interaction
NPHP1	NPHP4	biogrid_interaction, intact, string_interaction
NPHP1	OFD1	string_interaction
NPHP1	TMEM231	string_interaction
NPHP3	NPHP4	string_interaction
OFD1	TBC1D31	intact
ROBO1	ROBO2	intact
ROBO1	SLIT2	intact, string_interaction
ROBO1	SLIT3	string_interaction
ROBO1	SRGAP1	biogrid_interaction, intact, string_interaction
ROBO2	SLIT2	string_interaction
ROBO2	SLIT3	string_interaction
ROBO2	SRGAP1	string_interaction
SALL1	SALL4	intact
SALL1	SIX2	string_interaction
SLIT2	SRGAP1	string_interaction
SLIT3	SRGAP1	string_interaction

Structural data

PDB: 46 · AlphaFold-only: 27 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACE	P12821	97
EFTUD2	Q15029	68
CDC5L	Q99459	37
NOTCH1	P46531	29
TRAP1	Q12931	24
DHX8	Q14562	14
SALL4	Q9UJQ4	13
ROBO1	Q9Y6N7	12
KMT2D	O14686	11
ACTG1	P63261	10
EMC1	Q8N766	10
CHD1L	Q86WJ1	7
JAG1	P78504	7
LIFR	P42702	6
ROBO2	Q9HCK4	6
CACNA1D	Q01668	6
KCNT1	Q5JUK3	6
BCOR	Q6W2J9	5
MED13	Q9UHV7	5
BMP7	P18075	4
SLIT2	O94813	4
TRIO	O75962	4
GET1	O00258	4
COL4A1	P02462	4
NKX2-5	P52952	4
HNF1B	P35680	3
MED12	Q93074	3
SHANK3	Q9BYB0	3
CDON	Q4KMG0	3
KAT6B	Q8WYB5	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM231	Q9H6L2	88.65
VWA2	Q5GFL6	86.02
HPSE2	Q8WWQ2	82.90
HSP90B2P	Q58FF3	82.17
SLIT3	O75094	80.48
CTU2	Q2VPK5	80.27
UPK3A	O75631	78.77
TBC1D31	Q96DN5	76.36
SIX2	Q9NPC8	75.99
FREM1	Q5H8C1	75.75
SRGAP1	Q7Z6B7	73.49
GREB1L	Q9C091	72.90
NPHP4	O75161	72.44
SMAD6	O43541	72.34
GDF6	Q6KF10	70.88
OFD1	O75665	68.41
TBX6	O95947	66.18
ZMYM2	Q9UBW7	61.50
WDR62	O43379	61.19
TBX18	O95935	61.09
GATA5	Q9BWX5	59.91
SOX5	P35711	58.95
FOXC1	Q12948	56.09
SALL1	Q9NSC2	49.54
TRPS1	Q9UHF7	49.12
FRAS1	Q86XX4
FREM2	Q5SZK8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 377. Enrichment computed across 85 evidence-associated genes (57 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 57 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the ureteric bud	7	61.0×	5e-09	SIX2, SLIT2, ROBO2, SALL1, FOXC1, PAX2, RET
Kidney development	5	71.5×	9e-07	SIX2, SLIT2, ROBO2, SALL1, JAG1
Developmental Biology	17	4.3×	2e-05	BMP7, SIX2, SLIT2, SLIT3, SRGAP1, ROBO1, ROBO2, SALL1 (+9 more)
Regulation of commissural axon pathfinding by SLIT and ROBO	4	66.8×	3e-05	SLIT2, SLIT3, ROBO1, ROBO2
Defective LFNG causes SCDO3	3	120.2×	9e-05	NOTCH1, NOTCH2, NOTCH4
Pre-NOTCH Processing in the Endoplasmic Reticulum	3	100.2×	1e-04	NOTCH1, NOTCH2, NOTCH4
Inactivation of CDC42 and RAC1	3	75.1×	3e-04	SLIT2, SRGAP1, ROBO1
Nephron development	3	46.2×	0.002	HNF1B, JAG1, PAX2
Activation of RAC1	3	42.9×	0.002	SLIT2, ROBO1, PAK3
Pre-NOTCH Processing in Golgi	3	33.4×	0.003	NOTCH1, NOTCH2, NOTCH4
Formation of the nephric duct	3	33.4×	0.003	GATA3, PAX2, RET
Signaling by ROBO receptors	5	10.9×	0.003	SLIT2, SLIT3, SRGAP1, ROBO1, ROBO2
NOTCH4 Intracellular Domain Regulates Transcription	3	30.1×	0.004	NOTCH1, NOTCH2, NOTCH4
SLIT2:ROBO1 increases RHOA activity	2	100.2×	0.004	SLIT2, ROBO1
Regulation of cortical dendrite branching	2	80.1×	0.006	ROBO1, ROBO2
Axon guidance	7	5.5×	0.006	SLIT2, SLIT3, SRGAP1, ROBO1, ROBO2, CACNA1D, ACTG1
Netrin-1 signaling	3	23.1×	0.006	SLIT2, SLIT3, ROBO1
Notch-HLH transcription pathway	3	21.5×	0.007	NOTCH1, NOTCH2, NOTCH4
Nervous system development	7	5.3×	0.007	SLIT2, SLIT3, SRGAP1, ROBO1, ROBO2, CACNA1D, ACTG1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	2	57.2×	0.010	JAG1, NOTCH1
Formation of intermediate mesoderm	2	50.1×	0.012	FOXC1, PAX2
Role of ABL in ROBO-SLIT signaling	2	44.5×	0.015	SLIT2, ROBO1
RHOU GTPase cycle	3	14.7×	0.018	DLG5, ARHGEF6, PAK3
NOTCH4 Activation and Transmission of Signal to the Nucleus	2	36.4×	0.021	JAG1, NOTCH4
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	2	30.8×	0.028	SALL1, SALL4
RUNX3 regulates NOTCH signaling	2	28.6×	0.031	JAG1, NOTCH1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	3	11.3×	0.032	MED12, MED13, KMT2D
RAC1 GTPase cycle	5	5.4×	0.032	SRGAP1, TRIO, JAG1, ARHGEF6, PAK3
Constitutive Signaling by NOTCH1 HD Domain Mutants	2	26.7×	0.032	JAG1, NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	2	25.0×	0.035	HNF1B, NOTCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 82 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aortic valve morphogenesis	10	52.7×	2e-12	SLIT2, SLIT3, ROBO1, ROBO2, GATA5, NKX2-5, GATA3, JAG1 (+2 more)
kidney development	12	20.6×	3e-10	SIX2, SALL1, HNF1B, UPK3A, BICC1, FREM2, ACE, GREB1L (+4 more)
pulmonary valve morphogenesis	7	79.9×	5e-10	SLIT2, ROBO1, ROBO2, JAG1, SMAD6, NOTCH1, NOTCH2
ureteric bud development	7	38.9×	1e-07	BMP7, SLIT2, ROBO2, SALL1, FOXC1, SMAD6, RET
heart development	12	11.5×	1e-07	BMP7, SALL1, MED12, TSC2, BICC1, BCOR, NKX2-5, FREM2 (+4 more)
anatomical structure morphogenesis	9	15.3×	1e-06	SIX2, TBX6, FRAS1, FREM1, FREM2, FOXC1, GATA3, SMAD6 (+1 more)
positive regulation of transcription by RNA polymerase II	22	4.0×	2e-06	BMP7, SALL1, TBX6, MED12, GATA5, SALL4, CDON, CDC5L (+14 more)
cell fate determination	5	57.1×	2e-06	GATA3, JAG1, NOTCH2, NOTCH4, PAX2
ventricular septum morphogenesis	6	31.6×	4e-06	SLIT2, SLIT3, ROBO1, ROBO2, NKX2-5, NOTCH1
branching morphogenesis of an epithelial tube	5	44.7×	8e-06	BMP7, SLIT2, HNF1B, NOTCH1, PKD1
positive regulation of DNA-templated transcription	15	5.1×	2e-05	BMP7, SALL1, TBX18, HNF1B, MED12, KAT6B, MED13, NKX2-5 (+7 more)
axon guidance	9	9.9×	2e-05	BMP7, SLIT2, SLIT3, ROBO2, TRIO, GATA3, NOTCH1, NOTCH2 (+1 more)
ureter maturation	3	154.1×	3e-05	GATA3, PAX2, RET
apoptotic process involved in luteolysis	3	154.1×	3e-05	SLIT2, SLIT3, ROBO2
cardiac septum morphogenesis	4	58.7×	3e-05	BMP7, NKX2-5, JAG1, NOTCH1
negative regulation of transcription by RNA polymerase II	18	3.9×	3e-05	SALL1, TBX18, TBX6, HNF1B, TRPS1, GATA5, SALL4, BCOR (+10 more)
atrioventricular node development	3	102.8×	1e-04	NKX2-5, NOTCH1, NOTCH2
Roundabout signaling pathway	3	102.8×	1e-04	SLIT2, SLIT3, ROBO1
ureter development	3	102.8×	1e-04	TBX18, NPHP3, PAX2
positive regulation of Notch signaling pathway	5	21.4×	2e-04	ROBO1, ROBO2, GATA5, JAG1, NOTCH1
negative regulation of chemokine-mediated signaling pathway	3	88.1×	2e-04	SLIT2, SLIT3, ROBO1
heart induction	3	77.1×	2e-04	ROBO1, ROBO2, GATA5
mesenchymal to epithelial transition involved in metanephros morphogenesis	3	77.1×	2e-04	SIX2, SALL1, PAX2
mesodermal cell fate specification	3	77.1×	2e-04	SIX2, TBX6, PAX2
negative regulation of canonical Wnt signaling pathway	7	10.1×	2e-04	TBX18, CDON, NPHP4, BICC1, NKX2-5, NOTCH1, NPHP3
outflow tract septum morphogenesis	4	31.6×	3e-04	ROBO1, ROBO2, NKX2-5, SMAD6
positive regulation of smooth muscle cell differentiation	3	68.5×	3e-04	NOTCH1, NOTCH2, NOTCH4
genitalia development	3	61.6×	5e-04	HNF1B, PKD1, PTPN11
metanephric collecting duct development	3	61.6×	5e-04	DLG5, PAX2, PKD1
mesonephros development	3	56.0×	6e-04	BMP7, GATA3, PAX2

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 7 · Undrugged: 68

Druggability breadth: 32 of 85 evidence-associated genes (38%) 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
CACNA1D	BEPRIDIL
KCNT1	BEPRIDIL
ACE	TELMISARTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4
ACE	31	4
TRAP1	9	3
KCNT1	2	4
MED12	1	2
EFTUD2	1	2
NOTCH1	1	2
BMP7	0	0
SIX2	0	0
SLIT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1D, KCNT1
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D, KCNT1
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
ACE	304	Binding:288, Functional:8, ADMET:5, Unclassified:3
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2
TRAP1	94	Binding:94
KCNT1	24	Binding:24
NOTCH1	23	Binding:19, ADMET:4
KAT6B	22	Binding:20, Functional:2
SALL4	12	Binding:12
KMT2D	11	Binding:11
EFTUD2	8	Binding:8
LIFR	6	Binding:6
ARHGEF6	6	Binding:6
MED12	6	Binding:6
CHD1L	4	Binding:4
TRIO	2	Binding:2
BCOR	2	Binding:2
NOTCH2	2	Binding:2
NOTCH4	2	Binding:2
TSC2	1	Binding:1
CDC5L	1	Binding:1
DHX8	1	Binding:1
EMC1	1	Binding:1
JAG1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase
ACE	3.4.15.1	peptidyl-dipeptidase A
DHX8	3.6.4.13	RNA helicase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1D	233
ACE	304

Pharmacogenomics

Cohort genes with a PharmGKB record: 73; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	CACNA1D, KCNT1
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D, KCNT1
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CACNA1D, KCNT1, ACE
B	Phased (≥1) drug, not yet approved	4	MED12, TRAP1, EFTUD2, NOTCH1
C	Druggable family + PDB, no drug	6	LIFR, ROBO1, ROBO2, TRIO, CDON, DHX8
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	62	BMP7, SIX2, SLIT2, SLIT3, TBC1D1, ZMYM2, SRGAP1, CHD1L, TSHZ3, TBX6 (+52 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MED13	0	MED12
JAG1	1	NOTCH1
BMP7	0	—
SIX2	0	—
SLIT2	0	—
SLIT3	0	—
TBC1D1	0	—
ZMYM2	0	—
SRGAP1	0	—
CHD1L	4	—
TSHZ3	0	—
LIFR	6	—
TBX6	0	—
UPK3A	0	—
VWA2	0	—
BCORL1	0	—
DLG5	0	—
SHROOM4	0	—
TBC1D31	0	—
ARHGEF6	6	—
ROBO1	0	—
ROBO2	0	—
SALL1	0	—
SOX5	0	—
TBX18	0	—
HNF1B	0	—
HSP90B2P	0	—
TRIO	2	—
TRPS1	0	—
TSC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT