pseudohypoaldosteronism type 2E

Summary

pseudohypoaldosteronism type 2E (MONDO:0013782) is a disease caused by CUL3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CUL3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 167

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism type 2E
Mondo ID	MONDO:0013782
OMIM	614496
Orphanet	300530
ICD-11	1263491925
UMLS	C3469606
MedGen	483336
GARD	0017373
Is cancer (heuristic)	no

Also known as: CUL3 pseudohypoaldosteronism type 2 · Cul3 pseudohypoaldosteronism type 2 · PHA2E · pseudohypoaldosteronism type 2 caused by mutation in CUL3 · pseudohypoaldosteronism type 2 caused by mutation in Cul3 · pseudohypoaldosteronism, type IIE

Data availability: 167 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › pseudohypoaldosteronism › inherited pseudohypoaldosteronism › pseudohypoaldosteronism type 2 › pseudohypoaldosteronism type 2E

Related subtypes (4): pseudohypoaldosteronism type 2A, pseudohypoaldosteronism type 2B, pseudohypoaldosteronism type 2C, pseudohypoaldosteronism type 2D

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

167 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 34 benign, 10 pathogenic, 9 benign/likely benign, 8 conflicting classifications of pathogenicity, 7 likely pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100515	NM_003590.5(CUL3):c.1207-12T>G	CUL3	Pathogenic	no assertion criteria provided
100516	NM_003590.5(CUL3):c.1207-1G>A	CUL3	Pathogenic	no assertion criteria provided
100517	NM_003590.5(CUL3):c.1207-26A>G	CUL3	Pathogenic	criteria provided, single submitter
100518	NM_003590.5(CUL3):c.1207-28T>G	CUL3	Pathogenic	no assertion criteria provided
100519	NM_003590.5(CUL3):c.1207-3C>T	CUL3	Pathogenic	no assertion criteria provided
100520	NM_003590.5(CUL3):c.1207-5T>A	CUL3	Pathogenic	no assertion criteria provided
30323	NM_003590.5(CUL3):c.1238A>G (p.Asp413Gly)	CUL3	Pathogenic	no assertion criteria provided
3254545	NM_003590.5(CUL3):c.1312A>G (p.Arg438Gly)	CUL3	Pathogenic	criteria provided, single submitter
503870	NM_003590.5(CUL3):c.493_494del (p.Leu165fs)	CUL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523862	NM_003590.5(CUL3):c.739C>T (p.Arg247Ter)	CUL3	Pathogenic	criteria provided, multiple submitters, no conflicts
975925	NM_003590.5(CUL3):c.641C>G (p.Ala214Gly)	CUL3	Pathogenic	criteria provided, single submitter
2441683	NM_003590.5(CUL3):c.1629_1630del (p.His543fs)	CUL3	Likely pathogenic	criteria provided, single submitter
3585703	NM_003590.5(CUL3):c.1882dup (p.Val628fs)	CUL3	Likely pathogenic	criteria provided, single submitter
3585721	NM_003590.5(CUL3):c.427G>T (p.Gly143Ter)	CUL3	Likely pathogenic	criteria provided, single submitter
3767102	NM_003590.5(CUL3):c.144_145del (p.Asn48fs)	CUL3	Likely pathogenic	criteria provided, single submitter
4293125	NM_003590.5(CUL3):c.1895del (p.Gln632fs)	CUL3	Likely pathogenic	criteria provided, single submitter
4293424	NM_003590.5(CUL3):c.1377+4A>G	CUL3	Likely pathogenic	criteria provided, single submitter
4526517	NM_003590.5(CUL3):c.1310C>T (p.Ala437Val)	CUL3	Likely pathogenic	criteria provided, single submitter
1679660	NM_003590.5(CUL3):c.563A>G (p.Gln188Arg)	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2174644	NM_003590.5(CUL3):c.137G>A (p.Arg46His)	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334599	NM_003590.5(CUL3):c.*2272T>C	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334603	NM_003590.5(CUL3):c.*2130A>G	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334622	NM_003590.5(CUL3):c.*294A>G	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895282	NM_003590.5(CUL3):c.1036T>C (p.Leu346=)	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898341	NM_003590.5(CUL3):c.-246C>T	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
974891	NM_003590.5(CUL3):c.1358dup (p.Asn453fs)	CUL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
100526	NM_003590.5(CUL3):c.1377+3A>G	CUL3	Uncertain significance	criteria provided, single submitter
1175991	NM_003590.5(CUL3):c.532G>A (p.Val178Ile)	CUL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805100	NM_003590.5(CUL3):c.2092G>A (p.Asp698Asn)	CUL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2399057	NM_003590.5(CUL3):c.1849C>G (p.Gln617Glu)	CUL3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
CUL3	Strong	Autosomal dominant	pseudohypoaldosteronism type 2E	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CUL3	Orphanet:300530	Pseudohypoaldosteronism type 2E
CUL3	Orphanet:528084	Non-specific syndromic intellectual disability

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
CUL3	HGNC:2553	ENSG00000036257	Q13618	Cullin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CUL3	Cullin-3	Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CUL3	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology

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
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CUL3	296	ubiquitous	marker	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL3	9,954

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CUL3	Q13618	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
RHOBTB3 ATPase cycle	1	1142.0×	0.008	CUL3
RHOBTB2 GTPase cycle	1	475.8×	0.008	CUL3
RHOBTB1 GTPase cycle	1	475.8×	0.008	CUL3
Degradation of DVL	1	237.9×	0.009	CUL3
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.009	CUL3
Regulation of RAS by GAPs	1	193.6×	0.009	CUL3
Hedgehog ‘on’ state	1	158.6×	0.010	CUL3
KEAP1-NFE2L2 pathway	1	120.2×	0.011	CUL3
Potential therapeutics for SARS	1	114.2×	0.011	CUL3
Neddylation	1	47.4×	0.023	CUL3
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	CUL3

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
trophectodermal cellular morphogenesis	1	8426.0×	0.002	CUL3
liver morphogenesis	1	8426.0×	0.002	CUL3
regulation protein catabolic process at postsynapse	1	5617.3×	0.002	CUL3
positive regulation of mitotic cell cycle phase transition	1	5617.3×	0.002	CUL3
nuclear protein quality control by the ubiquitin-proteasome system	1	4213.0×	0.002	CUL3
stem cell division	1	1872.4×	0.003	CUL3
embryonic cleavage	1	1685.2×	0.003	CUL3
fibroblast apoptotic process	1	1532.0×	0.003	CUL3
regulation of cellular response to insulin stimulus	1	1532.0×	0.003	CUL3
positive regulation of mitotic metaphase/anaphase transition	1	1203.7×	0.003	CUL3
negative regulation of Rho protein signal transduction	1	766.0×	0.004	CUL3
stress fiber assembly	1	766.0×	0.004	CUL3
gastrulation	1	702.2×	0.004	CUL3
anaphase-promoting complex-dependent catabolic process	1	702.2×	0.004	CUL3
COPII vesicle coat assembly	1	702.2×	0.004	CUL3
negative regulation of type I interferon production	1	495.6×	0.005	CUL3
positive regulation of cytokinesis	1	401.2×	0.006	CUL3
mitotic metaphase chromosome alignment	1	383.0×	0.006	CUL3
cell projection organization	1	374.5×	0.006	CUL3
intrinsic apoptotic signaling pathway	1	358.6×	0.006	CUL3
protein monoubiquitination	1	343.9×	0.006	CUL3
cellular response to amino acid stimulus	1	306.4×	0.006	CUL3
positive regulation of TORC1 signaling	1	295.6×	0.006	CUL3
protein destabilization	1	290.6×	0.006	CUL3
protein autoubiquitination	1	234.1×	0.007	CUL3
positive regulation of protein ubiquitination	1	213.3×	0.008	CUL3
G1/S transition of mitotic cell cycle	1	200.6×	0.008	CUL3
protein K48-linked ubiquitination	1	168.5×	0.009	CUL3
integrin-mediated signaling pathway	1	160.5×	0.009	CUL3
cellular response to oxidative stress	1	154.6×	0.009	CUL3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CUL3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CUL3	7	Binding:7

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CUL3

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)
CUL3	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.