pseudohypoaldosteronism type 2A

Summary

pseudohypoaldosteronism type 2A (MONDO:0007772) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism type 2A
Mondo ID	MONDO:0007772
OMIM	145260
Orphanet	88938
ICD-11	646091849
SNOMED CT	703254001
UMLS	C1840389
MedGen	327088
GARD	0016775
Is cancer (heuristic)	no

Also known as: PHA2A · pseudohypoaldosteronism, type IIA

Data availability: 40 ClinVar variants.

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 2A

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

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

40 retrieved; paginated sample, class counts are floors:

27 pathogenic, 6 uncertain significance, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

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
100521	NM_003590.5(CUL3):c.1236G>A (p.Leu412=)	CUL3	Pathogenic	no assertion criteria provided
100522	NM_003590.5(CUL3):c.1376A>G (p.Lys459Arg)	CUL3	Pathogenic	no assertion criteria provided
100523	NM_003590.5(CUL3):c.1376_1377+4del	CUL3	Pathogenic	no assertion criteria provided
100524	NM_003590.5(CUL3):c.1377+1dup	CUL3	Pathogenic	no assertion criteria provided
100525	NM_003590.5(CUL3):c.1377+1G>C	CUL3	Pathogenic	no assertion criteria provided
30323	NM_003590.5(CUL3):c.1238A>G (p.Asp413Gly)	CUL3	Pathogenic	no assertion criteria provided
100527	NM_017415.3(KLHL3):c.1410G>A (p.Trp470Ter)	KLHL3	Pathogenic	no assertion criteria provided
100528	NM_017415.3(KLHL3):c.721del (p.Leu241fs)	KLHL3	Pathogenic	no assertion criteria provided
100529	NM_017415.3(KLHL3):c.753+1G>A	KLHL3	Pathogenic	no assertion criteria provided
100531	NM_017415.3(KLHL3):c.1480G>A (p.Ala494Thr)	KLHL3	Pathogenic	no assertion criteria provided
100532	NM_017415.3(KLHL3):c.230C>A (p.Ala77Glu)	KLHL3	Pathogenic	no assertion criteria provided
100533	NM_017415.3(KLHL3):c.491G>T (p.Cys164Phe)	KLHL3	Pathogenic	no assertion criteria provided
100534	NM_017415.3(KLHL3):c.254A>C (p.Glu85Ala)	KLHL3	Pathogenic	no assertion criteria provided
100538	NM_017415.3(KLHL3):c.232A>G (p.Met78Val)	KLHL3	Pathogenic	no assertion criteria provided
100539	NM_017415.3(KLHL3):c.1501C>A (p.Pro501Thr)	KLHL3	Pathogenic	no assertion criteria provided
100540	NM_017415.3(KLHL3):c.430C>T (p.Gln144Ter)	KLHL3	Pathogenic	no assertion criteria provided
100541	NM_017415.3(KLHL3):c.926A>G (p.Gln309Arg)	KLHL3	Pathogenic	criteria provided, single submitter
30516	NM_017415.3(KLHL3):c.965T>G (p.Phe322Cys)	KLHL3	Pathogenic	no assertion criteria provided
30517	NM_017415.3(KLHL3):c.1229C>T (p.Ser410Leu)	KLHL3	Pathogenic	no assertion criteria provided
30518	NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)	KLHL3	Pathogenic	criteria provided, multiple submitters, no conflicts
30519	NM_017415.3(KLHL3):c.718C>T (p.Arg240Ter)	KLHL3	Pathogenic	criteria provided, multiple submitters, no conflicts
30520	NM_017415.3(KLHL3):c.1007G>T (p.Arg336Ile)	KLHL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30523	NM_017415.3(KLHL3):c.1298G>A (p.Ser433Asn)	KLHL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
266041	NM_003590.5(CUL3):c.1377G>A (p.Lys459=)	CUL3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
KLHL3	Orphanet:300525	Pseudohypoaldosteronism type 2D

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CUL3	HGNC:2553	ENSG00000036257	Q13618	Cullin-3	clinvar
KLHL3	HGNC:6354	ENSG00000146021	Q9UH77	Kelch-like protein 3	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.
KLHL3	Kelch-like protein 3	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CUL3	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
KLHL3	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
male germ cell	1
sperm	1
cerebellar vermis	1
cerebellum	1
middle temporal gyrus	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
KLHL3	262	broad	marker	cerebellar vermis, middle temporal gyrus, cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL3	9,954
KLHL3	947

Intra-cohort edges

A	B	Sources
CUL3	KLHL3	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CUL3	Q13618	30
KLHL3	Q9UH77	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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
Neddylation	2	47.4×	0.006	CUL3, KLHL3
Antigen processing: Ubiquitination & Proteasome degradation	2	37.2×	0.006	CUL3, KLHL3
RHOBTB3 ATPase cycle	1	571.0×	0.009	CUL3
RHOBTB2 GTPase cycle	1	237.9×	0.013	CUL3
RHOBTB1 GTPase cycle	1	237.9×	0.013	CUL3
Degradation of DVL	1	119.0×	0.020	CUL3
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	114.2×	0.020	CUL3
Regulation of RAS by GAPs	1	96.8×	0.021	CUL3
Hedgehog ‘on’ state	1	79.3×	0.022	CUL3
KEAP1-NFE2L2 pathway	1	60.1×	0.025	CUL3
Potential therapeutics for SARS	1	57.1×	0.025	CUL3
Class I MHC mediated antigen processing & presentation	1	35.0×	0.038	KLHL3
Adaptive Immune System	1	14.9×	0.081	KLHL3
Post-translational protein modification	1	9.6×	0.116	KLHL3
Immune System	1	6.5×	0.155	KLHL3
Metabolism of proteins	1	6.2×	0.155	KLHL3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein K48-linked ubiquitination	2	168.5×	0.002	CUL3, KLHL3
trophectodermal cellular morphogenesis	1	4213.0×	0.002	CUL3
distal tubule morphogenesis	1	4213.0×	0.002	KLHL3
liver morphogenesis	1	4213.0×	0.002	CUL3
gene expression	2	79.9×	0.002	CUL3, KLHL3
ubiquitin-dependent protein catabolic process	2	74.2×	0.002	CUL3, KLHL3
regulation protein catabolic process at postsynapse	1	2808.7×	0.002	CUL3
positive regulation of mitotic cell cycle phase transition	1	2808.7×	0.002	CUL3
proteasome-mediated ubiquitin-dependent protein catabolic process	2	52.2×	0.002	CUL3, KLHL3
nuclear protein quality control by the ubiquitin-proteasome system	1	2106.5×	0.002	CUL3
protein ubiquitination	2	41.4×	0.002	CUL3, KLHL3
monoatomic ion homeostasis	1	1203.7×	0.003	KLHL3
stem cell division	1	936.2×	0.004	CUL3
embryonic cleavage	1	842.6×	0.004	CUL3
fibroblast apoptotic process	1	766.0×	0.004	CUL3
regulation of cellular response to insulin stimulus	1	766.0×	0.004	CUL3
positive regulation of mitotic metaphase/anaphase transition	1	601.9×	0.005	CUL3
renal sodium ion absorption	1	495.6×	0.005	KLHL3
negative regulation of Rho protein signal transduction	1	383.0×	0.006	CUL3
stress fiber assembly	1	383.0×	0.006	CUL3
potassium ion homeostasis	1	383.0×	0.006	KLHL3
gastrulation	1	351.1×	0.006	CUL3
anaphase-promoting complex-dependent catabolic process	1	351.1×	0.006	CUL3
COPII vesicle coat assembly	1	351.1×	0.006	CUL3
negative regulation of type I interferon production	1	247.8×	0.008	CUL3
positive regulation of cytokinesis	1	200.6×	0.009	CUL3
mitotic metaphase chromosome alignment	1	191.5×	0.009	CUL3
cell projection organization	1	187.2×	0.009	CUL3
intrinsic apoptotic signaling pathway	1	179.3×	0.009	CUL3
protein monoubiquitination	1	172.0×	0.009	CUL3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
KLHL3	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
KLHL3	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CUL3, KLHL3

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)
CUL3	7	—
KLHL3	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.