Renal hypodysplasia/aplasia 1

Summary

Renal hypodysplasia/aplasia 1 (MONDO:0024519) is a disease caused by ITGA8 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ITGA8 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 193

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal hypodysplasia/aplasia 1
Mondo ID	MONDO:0024519
OMIM	191830
UMLS	C1619700
MedGen	301437
GARD	0004791
Is cancer (heuristic)	no

Also known as: renal dysplasia, megalocystis, and sirenomelia · renal hypodysplasia/aplasia 1 · RHDA1 · Selig Benacerraf Greene syndrome

Data availability: 193 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 › renal agenesis › renal hypodysplasia/aplasia 1

Related subtypes (5): renal hypodysplasia/aplasia 2, bilateral renal agenesis, renal agenesis, unilateral, renal hypodysplasia/aplasia 3, renal hypodysplasia/aplasia 4

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

193 retrieved; paginated sample, class counts are floors:

67 conflicting classifications of pathogenicity, 56 uncertain significance, 36 benign/likely benign, 16 benign, 6 likely benign, 5 pathogenic, 5 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
126498	NM_003638.3(ITGA8):c.2982+2T>C	ITGA8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126499	NM_003638.3(ITGA8):c.1622_1626del (p.Glu541fs)	ITGA8	Pathogenic	no assertion criteria provided
126500	NM_003638.3(ITGA8):c.1219G>A (p.Gly407Arg)	ITGA8	Pathogenic	criteria provided, single submitter
1706540	NM_003638.3(ITGA8):c.2804dup (p.Val936fs)	ITGA8	Pathogenic	criteria provided, single submitter
3900017	NM_003638.3(ITGA8):c.467G>A (p.Trp156Ter)	ITGA8	Pathogenic	criteria provided, single submitter
4688183	NM_003638.3(ITGA8):c.2812C>T (p.Arg938Ter)	ITGA8	Pathogenic	criteria provided, multiple submitters, no conflicts
37102	NM_020975.6(RET):c.2410G>A (p.Val804Met)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324596	NM_003638.3(ITGA8):c.2626C>T (p.Gln876Ter)	ITGA8	Likely pathogenic	criteria provided, single submitter
2627439	NM_003638.3(ITGA8):c.1764+1G>A	ITGA8	Likely pathogenic	criteria provided, single submitter
3065947	NM_003638.3(ITGA8):c.1970+1G>A	ITGA8	Likely pathogenic	criteria provided, single submitter
3382277	NM_003638.3(ITGA8):c.158del (p.Lys53fs)	ITGA8	Likely pathogenic	criteria provided, single submitter
4278106	NM_003638.3(ITGA8):c.562C>T (p.Arg188Trp)	ITGA8	Likely pathogenic	criteria provided, single submitter
790274	NM_003638.3(ITGA8):c.840T>C (p.Ser280=)	ITGA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136095	NM_020975.6(RET):c.1158G>A (p.Ala386=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136103	NM_020975.6(RET):c.1699G>A (p.Asp567Asn)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136105	NM_020975.6(RET):c.1920C>T (p.Ala640=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136115	NM_020975.6(RET):c.3112A>G (p.Thr1038Ala)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136118	NM_020975.6(RET):c.3243T>C (p.Asp1081=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136121	NM_020975.6(RET):c.597C>T (p.Asn199=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13936	NM_020975.6(RET):c.2372A>T (p.Tyr791Phe)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13938	NM_020975.6(RET):c.2944C>T (p.Arg982Cys)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13955	NM_020975.6(RET):c.2332G>A (p.Val778Ile)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161358	NM_020975.6(RET):c.2081G>A (p.Arg694Gln)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183744	NM_020975.6(RET):c.3253A>G (p.Thr1085Ala)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184139	NM_020975.6(RET):c.957C>A (p.Leu319=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184140	NM_020975.6(RET):c.2523G>T (p.Pro841=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184368	NM_020975.6(RET):c.225G>A (p.Thr75=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188078	NM_020975.6(RET):c.972G>C (p.Trp324Cys)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215909	NM_020975.6(RET):c.1890C>T (p.Cys630=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215914	NM_020975.6(RET):c.2988G>A (p.Pro996=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 12 · 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
ITGA8	Strong	Autosomal recessive	renal hypodysplasia/aplasia 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITGA8	Orphanet:1848	Renal agenesis, bilateral
UPK3A	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome

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
ITGA8	HGNC:6144	ENSG00000077943	P53708	Integrin alpha-8	gencc,clinvar
UPK3A	HGNC:12580	ENSG00000100373	O75631	Uroplakin-3a	clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITGA8	Integrin alpha-8	Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures.
UPK3A	Uroplakin-3a	Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

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×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITGA8	Antibody/Immunoglobulin	yes		Integrin_alpha, FG-GAP, Int_alpha_beta-p
UPK3A	Other/Unknown	no		Uroplakin-3a, Uroplakin-3
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

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
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
gastrocnemius	1
mucosa of urinary bladder	1
muscle of leg	1
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITGA8	246	broad	marker	thoracic aorta, descending thoracic aorta, ascending aorta
UPK3A	126	broad	marker	gastrocnemius, mucosa of urinary bladder, muscle of leg
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203
ITGA8	1,613
UPK3A	508

Intra-cohort edges

A	B	Sources
RET	UPK3A	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ITGA8	P53708	85.08
UPK3A	O75631	78.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 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
Formation of the ureteric bud	2	496.5×	6e-05	ITGA8, RET
Kidney development	1	407.9×	0.015	ITGA8
Formation of the nephric duct	1	317.2×	0.015	RET
NPAS4 regulates expression of target genes	1	248.3×	0.015	RET
Elastic fibre formation	1	167.9×	0.015	ITGA8
TGF-beta receptor signaling activates SMADs	1	163.1×	0.015	ITGA8
Molecules associated with elastic fibres	1	154.3×	0.015	ITGA8
RET signaling	1	129.8×	0.015	RET
Signaling by TGF-beta Receptor Complex	1	100.2×	0.018	ITGA8
ECM proteoglycans	1	75.1×	0.021	ITGA8
Integrin cell surface interactions	1	67.2×	0.022	ITGA8
Signaling by TGFB family members	1	57.7×	0.023	ITGA8
Extracellular matrix organization	1	31.6×	0.037	ITGA8
RAF/MAP kinase cascade	1	30.5×	0.037	RET
Developmental Biology	1	7.2×	0.142	ITGA8
Signal Transduction	1	5.1×	0.187	ITGA8

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
embryonic epithelial tube formation	1	2808.7×	0.005	RET
posterior midgut development	1	2808.7×	0.005	RET
positive regulation of metanephric glomerulus development	1	1872.4×	0.005	RET
urea transport	1	1404.3×	0.005	UPK3A
ureter maturation	1	1404.3×	0.005	RET
urinary bladder development	1	1404.3×	0.005	UPK3A
Peyer’s patch morphogenesis	1	1404.3×	0.005	RET
GDF15-GFRAL signaling pathway	1	1404.3×	0.005	RET
kidney development	2	93.6×	0.005	ITGA8, UPK3A
lymphocyte migration into lymphoid organs	1	624.1×	0.008	RET
mesodermal cell differentiation	1	510.7×	0.008	ITGA8
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	510.7×	0.008	RET
positive regulation of cell size	1	432.1×	0.008	RET
glial cell-derived neurotrophic factor receptor signaling pathway	1	401.2×	0.008	RET
membrane protein proteolysis	1	351.1×	0.008	RET
positive regulation of cell adhesion mediated by integrin	1	351.1×	0.008	RET
smooth muscle tissue development	1	351.1×	0.008	ITGA8
water transport	1	330.4×	0.008	UPK3A
neuron cell-cell adhesion	1	330.4×	0.008	RET
enteric nervous system development	1	330.4×	0.008	RET
sodium ion homeostasis	1	312.1×	0.008	UPK3A
response to pain	1	295.6×	0.008	RET
regulation of axonogenesis	1	295.6×	0.008	RET
smooth muscle cell differentiation	1	295.6×	0.008	ITGA8
neuron maturation	1	267.5×	0.009	RET
potassium ion homeostasis	1	255.3×	0.009	UPK3A
positive regulation of transforming growth factor beta receptor signaling pathway	1	175.5×	0.012	ITGA8
metanephros development	1	170.2×	0.012	ITGA8
ureteric bud development	1	151.8×	0.013	RET
establishment of protein localization	1	144.0×	0.013	ITGA8

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
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
ITGA8	0	0
UPK3A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
ITGA8	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RET	1,586

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

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)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ITGA8
E	Difficult family or no structure, no drug	1	UPK3A

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)
ITGA8	3	—
UPK3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.