Autosomal dominant pseudohypoaldosteronism type 1

Summary

Autosomal dominant pseudohypoaldosteronism type 1 (MONDO:0008329) is a disease caused by NR3C2 (GenCC Definitive), with 3 cohort genes and 4 clinical trials. Top therapeutic interventions include metronidazole.

At a glance

• Prevalence: 1-9 / 100 000 (United Kingdom) [Orphanet-validated]
• Causal gene: NR3C2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 237
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.51	United Kingdom	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant pseudohypoaldosteronism type 1
Mondo ID	MONDO:0008329
OMIM	177735
Orphanet	171871
DOID	DOID:0060855
NCIT	C126810
UMLS	C1449842
MedGen	260623
GARD	0009145
Is cancer (heuristic)	no

Also known as: autosomal dominant pseudohypoaldosteronism type 1 · PHA1A · pseudohypoaldosteronism type 1 autosomal dominant · pseudohypoaldosteronism type 1, dominant · pseudohypoaldosteronism type i, autosomal dominant · pseudohypoaldosteronism, type I, autosomal dominant · renal PHA1 · renal pseudohypoaldosteronism type 1

Data availability: 237 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubule disorder › inherited renal tubular disease › pseudohypoaldosteronism type 1 › autosomal dominant pseudohypoaldosteronism type 1

Related subtypes (3): pseudohypoaldosteronism, type IB1, autosomal recessive, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive

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

237 retrieved; paginated sample, class counts are floors:

136 uncertain significance, 32 benign, 22 pathogenic, 12 likely pathogenic, 12 conflicting classifications of pathogenicity, 11 benign/likely benign, 9 likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
559557	NM_003590.5(CUL3):c.173A>G (p.Tyr58Cys)	CUL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678530	NM_000901.5(NR3C2):c.1819delinsTT (p.Gly607fs)	NR3C2	Pathogenic	criteria provided, single submitter
1809717	NM_000901.5(NR3C2):c.2194C>T (p.Arg732Ter)	NR3C2	Pathogenic	criteria provided, multiple submitters, no conflicts
3042426	NM_000901.5(NR3C2):c.2799+1G>A	NR3C2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3590196	NM_000901.5(NR3C2):c.1954C>T (p.Arg652Ter)	NR3C2	Pathogenic	criteria provided, single submitter
3906996	NM_000901.5(NR3C2):c.2532del (p.Met845fs)	NR3C2	Pathogenic	criteria provided, single submitter
430357	NM_000901.5(NR3C2):c.1951C>T (p.Arg651Ter)	NR3C2	Pathogenic	criteria provided, multiple submitters, no conflicts
623200	NM_000901.5(NR3C2):c.2755C>T (p.Gln919Ter)	NR3C2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8553	NM_000901.5(NR3C2):c.1004del (p.Ser335fs)	NR3C2	Pathogenic	no assertion criteria provided
8554	NM_000901.5(NR3C2):c.1375del (p.Ser459fs)	NR3C2	Pathogenic	no assertion criteria provided
8555	NM_000901.5(NR3C2):c.1609C>T (p.Arg537Ter)	NR3C2	Pathogenic	criteria provided, single submitter
8556	NM_000901.5(NR3C2):c.2365+3del	NR3C2	Pathogenic	no assertion criteria provided
8558	NM_000901.5(NR3C2):c.2871dup (p.Ala958fs)	NR3C2	Pathogenic	no assertion criteria provided
8560	NM_000901.5(NR3C2):c.1131dup (p.Glu378Ter)	NR3C2	Pathogenic	no assertion criteria provided
8561	NM_000901.5(NR3C2):c.315_322del (p.Met105fs)	NR3C2	Pathogenic	no assertion criteria provided
8562	NM_000901.5(NR3C2):c.1935C>A (p.Cys645Ter)	NR3C2	Pathogenic	no assertion criteria provided
8563	NM_000901.5(NR3C2):c.2327A>G (p.Gln776Arg)	NR3C2	Pathogenic	no assertion criteria provided
8564	NM_000901.5(NR3C2):c.1897G>A (p.Gly633Arg)	NR3C2	Pathogenic	no assertion criteria provided
8565	NM_000901.5(NR3C2):c.2936T>C (p.Leu979Pro)	NR3C2	Pathogenic	no assertion criteria provided
8566	NM_000901.5(NR3C2):c.488C>G (p.Ser163Ter)	NR3C2	Pathogenic	no assertion criteria provided
8567	NM_000901.5(NR3C2):c.2839C>T (p.Arg947Ter)	NR3C2	Pathogenic	criteria provided, single submitter
8568	NM_000901.5(NR3C2):c.1308T>A (p.Cys436Ter)	NR3C2	Pathogenic	no assertion criteria provided
8570	NM_000901.5(NR3C2):c.2024C>G (p.Ser675Ter)	NR3C2	Pathogenic	no assertion criteria provided
8571	NM_000901.5(NR3C2):c.2453C>T (p.Ser818Leu)	NR3C2	Pathogenic	criteria provided, single submitter
8572	NM_000901.5(NR3C2):c.2915A>G (p.Glu972Gly)	NR3C2	Pathogenic	no assertion criteria provided
1697205	NC_000004.11:g.(?149081621)(151082561_?)del	DCLK2	Likely pathogenic	criteria provided, single submitter
1065468	NM_000901.5(NR3C2):c.2767C>T (p.Gln923Ter)	NR3C2	Likely pathogenic	criteria provided, single submitter
1339260	NM_000901.5(NR3C2):c.1799C>A (p.Ser600Ter)	NR3C2	Likely pathogenic	criteria provided, single submitter
1342478	NM_000901.5(NR3C2):c.102del (p.Glu35fs)	NR3C2	Likely pathogenic	criteria provided, single submitter
1709131	NM_000901.5(NR3C2):c.2657T>A (p.Leu886His)	NR3C2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
NR3C2	Definitive	Autosomal dominant	autosomal dominant pseudohypoaldosteronism type 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR3C2	Orphanet:171871	Renal pseudohypoaldosteronism type 1
CUL3	Orphanet:300530	Pseudohypoaldosteronism type 2E
CUL3	Orphanet:528084	Non-specific syndromic intellectual disability

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
NR3C2	HGNC:7979	ENSG00000151623	P08235	Mineralocorticoid receptor	gencc,clinvar
DCLK2	HGNC:19002	ENSG00000170390	Q8N568	Serine/threonine-protein kinase DCLK2	clinvar
CUL3	HGNC:2553	ENSG00000036257	Q13618	Cullin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR3C2	Mineralocorticoid receptor	Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol.
DCLK2	Serine/threonine-protein kinase DCLK2	Protein kinase with a significantly reduced C(a2+)/CAM affinity and dependence compared to other members of the CaMK family.
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: 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
Nuclear receptor	1	128.6×	0.023
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR3C2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Znf_NHR/GATA
DCLK2	Kinase	yes		Prot_kinase_dom, Doublecortin_dom, Ser/Thr_kinase_AS
CUL3	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology

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
colonic mucosa	1
endothelial cell	1
mucosa of sigmoid colon	1
cortical plate	1
oocyte	1
secondary oocyte	1
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR3C2	277	broad	marker	endothelial cell, colonic mucosa, mucosa of sigmoid colon
DCLK2	183	ubiquitous	marker	oocyte, secondary oocyte, cortical plate
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
NR3C2	2,188
DCLK2	896

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR3C2	P08235	30
CUL3	Q13618	30

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DCLK2	Q8N568	70.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
RHOBTB3 ATPase cycle	1	571.0×	0.021	CUL3
RHOBTB2 GTPase cycle	1	237.9×	0.021	CUL3
RHOBTB1 GTPase cycle	1	237.9×	0.021	CUL3
SUMOylation of intracellular receptors	1	167.9×	0.021	NR3C2
Degradation of DVL	1	119.0×	0.021	CUL3
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	114.2×	0.021	CUL3
Nuclear Receptor transcription pathway	1	100.2×	0.021	NR3C2
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.021	NR3C2
Regulation of RAS by GAPs	1	96.8×	0.021	CUL3
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.021	NR3C2
SUMOylation	1	81.6×	0.021	NR3C2
Hedgehog ‘on’ state	1	79.3×	0.021	CUL3
KEAP1-NFE2L2 pathway	1	60.1×	0.025	CUL3
Potential therapeutics for SARS	1	57.1×	0.025	CUL3
Neddylation	1	23.7×	0.056	CUL3
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.063	CUL3
Cellular responses to stress	1	18.4×	0.063	NR3C2
Cellular responses to stimuli	1	15.7×	0.070	NR3C2
Post-translational protein modification	1	9.6×	0.107	NR3C2
Metabolism of proteins	1	6.2×	0.155	NR3C2

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
trophectodermal cellular morphogenesis	1	2808.7×	0.007	CUL3
liver morphogenesis	1	2808.7×	0.007	CUL3
regulation protein catabolic process at postsynapse	1	1872.4×	0.007	CUL3
positive regulation of mitotic cell cycle phase transition	1	1872.4×	0.007	CUL3
nuclear protein quality control by the ubiquitin-proteasome system	1	1404.3×	0.007	CUL3
pyramidal neuron development	1	702.2×	0.009	DCLK2
nuclear receptor-mediated steroid hormone signaling pathway	1	702.2×	0.009	NR3C2
stem cell division	1	624.1×	0.009	CUL3
embryonic cleavage	1	561.7×	0.009	CUL3
fibroblast apoptotic process	1	510.7×	0.009	CUL3
regulation of cellular response to insulin stimulus	1	510.7×	0.009	CUL3
positive regulation of mitotic metaphase/anaphase transition	1	401.2×	0.011	CUL3
negative regulation of protein localization to nucleus	1	280.9×	0.012	DCLK2
negative regulation of Rho protein signal transduction	1	255.3×	0.012	CUL3
stress fiber assembly	1	255.3×	0.012	CUL3
gastrulation	1	234.1×	0.012	CUL3
anaphase-promoting complex-dependent catabolic process	1	234.1×	0.012	CUL3
COPII vesicle coat assembly	1	234.1×	0.012	CUL3
negative regulation of type I interferon production	1	165.2×	0.017	CUL3
positive regulation of cytokinesis	1	133.8×	0.018	CUL3
mitotic metaphase chromosome alignment	1	127.7×	0.018	CUL3
cell projection organization	1	124.8×	0.018	CUL3
intrinsic apoptotic signaling pathway	1	119.5×	0.018	CUL3
protein localization to nucleus	1	117.0×	0.018	DCLK2
protein monoubiquitination	1	114.6×	0.018	CUL3
cellular response to amino acid stimulus	1	102.1×	0.019	CUL3
positive regulation of TORC1 signaling	1	98.5×	0.019	CUL3
protein destabilization	1	96.8×	0.019	CUL3
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.021	NR3C2
protein autoubiquitination	1	78.0×	0.022	CUL3

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
NR3C2	PROGESTERONE
DCLK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR3C2	24	4
DCLK2	9	4
CUL3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	NR3C2
EPLERENONE	4	NR3C2
MIFEPRISTONE	4	NR3C2
PREDNISOLONE	4	NR3C2
BUDESONIDE	4	NR3C2
SPIRONOLACTONE	4	NR3C2
FLUTICASONE PROPIONATE	4	NR3C2
FLUTICASONE FUROATE	4	NR3C2
HYDROCORTISONE BUTYRATE	4	NR3C2
FINERENONE	4	NR3C2
DEXAMETHASONE	4	NR3C2
HYDROCORTISONE	4	NR3C2
MEDROXYPROGESTERONE ACETATE	4	NR3C2
FEDRATINIB	4	DCLK2
RUXOLITINIB	4	DCLK2
SUNITINIB	4	DCLK2
CRIZOTINIB	4	DCLK2
CORTICOSTERONE	3	NR3C2
ASOPRISNIL	3	NR3C2
BALCINRENONE	3	NR3C2
LESTAURTINIB	3	DCLK2
METRIBOLONE	2	NR3C2
ONAPRISTONE	2	NR3C2
MT-3995	2	NR3C2
ALDOSTERONE	2	NR3C2
STANOLONE	2	NR3C2
LY2623091	2	NR3C2
TUROFEXORATE ISOPROPYL	2	NR3C2
SU-014813	2	DCLK2
AT-7519	2	DCLK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR3C2	286	Binding:195, Functional:89, ADMET:2
DCLK2	216	Binding:216
CUL3	7	Binding:7

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NR3C2	286
DCLK2	216

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)
PROGESTERONE	4	NR3C2
EPLERENONE	4	NR3C2
MIFEPRISTONE	4	NR3C2
PREDNISOLONE	4	NR3C2
BUDESONIDE	4	NR3C2
SPIRONOLACTONE	4	NR3C2
FLUTICASONE PROPIONATE	4	NR3C2
FLUTICASONE FUROATE	4	NR3C2
HYDROCORTISONE BUTYRATE	4	NR3C2
FINERENONE	4	NR3C2
DEXAMETHASONE	4	NR3C2
HYDROCORTISONE	4	NR3C2
MEDROXYPROGESTERONE ACETATE	4	NR3C2
FEDRATINIB	4	DCLK2
RUXOLITINIB	4	DCLK2
SUNITINIB	4	DCLK2
CRIZOTINIB	4	DCLK2
CORTICOSTERONE	3	NR3C2
ASOPRISNIL	3	NR3C2
BALCINRENONE	3	NR3C2
LESTAURTINIB	3	DCLK2
METRIBOLONE	2	NR3C2
ONAPRISTONE	2	NR3C2
MT-3995	2	NR3C2
ALDOSTERONE	2	NR3C2
STANOLONE	2	NR3C2
LY2623091	2	NR3C2
TUROFEXORATE ISOPROPYL	2	NR3C2
SU-014813	2	DCLK2
AT-7519	2	DCLK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NR3C2, DCLK2
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: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	3
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06435936	PHASE1	ACTIVE_NOT_RECRUITING	A Study to Assess the Safety of SAB-176 to Prevent the Flu, Given IM in Healthy Adults Compared With Placebo
NCT03630094	PHASE1	COMPLETED	Plasma and Intrapulmonary Concentrations Study of WCK 5222
NCT06806995	PHASE1	COMPLETED	A Single-center, Open-label, Study Evaluating Safety and Pharmacokinetics of Single Doses of Zidebactam-Cefepime and Metronidazole Alone or in Combination.
NCT03931668	EARLY_PHASE1	UNKNOWN	Tolerance, PK and PD Effects Study of TPN-672 in Chinese Healthy Volunteers

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METRONIDAZOLE	4	1