Hyperaldosteronism

Summary

Hyperaldosteronism (MONDO:0003009) is a disease with 1 cohort gene (15 GWAS associations across 5 studies) and 30 clinical trials. Top therapeutic interventions include bromocriptine, eplerenone, and spironolactone.

At a glance

• Cohort genes: 1
• GWAS associations: 15
• ClinVar variants: 2
• Clinical trials: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperaldosteronism
Mondo ID	MONDO:0003009
EFO	EFO:0009452
MeSH	D006929
DOID	DOID:446
ICD-10-CM	E26
ICD-11	1937534076
SNOMED CT	88213004
UMLS	C0020428
MedGen	6960
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants · 15 GWAS associations (5 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism

Subtypes (1): primary aldosteronism

Genetics & variants

GWAS landscape

15 GWAS associations across 5 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6563624	8e-23	B3GLCT - RXFP2	T	0.4
chr13:32136829	2e-19		A	0.53
rs574711622	3e-15	KLF12	C	3.85
rs184179564	5e-13	RHPN1	C	2.91
rs564420311	3e-12	SLC6A2	T	2.96
rs184687038	4e-12	EXD2	C	1.8
rs193021393	8e-12	LUZP2 - RPL36AP40	C	2.37
rs185095296	1e-11	IQCE	C	1.69
rs112026708	2e-11	PCDH7 - LINC02497	C	3.05
rs192451515	2e-11	IGLVV-58 - BMP6P1	A	4.49
rs182529943	2e-11	EXOC1L - EXOC1	G	2.99
rs547043053	2e-11	RN7SKP191 - SLC44A1	T	3.1
rs563018585	3e-11	VAPA - LINC01254	G	2.64
rs185811454	4e-11	POT1-AS1 - GRM8	T	3.12
rs7237205	7e-09	MIR187 - MIR3929	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475695	Verma A	2024	711	450,427	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477343	Verma A	2024	677	121,041	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479900	Verma A	2024	677	121,041	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651426	Liu TY	2025	203	224,577	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90435729	Zhou W	2018	76	405,386	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	14

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	12
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	6
intron_variant	6
unknown	1
3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6563624	13	31619754	T>A,C,G	0.457	intergenic_variant	B3GLCT - RXFP2	8e-23	Tier 4: intronic/intergenic
chr13:32136829				0.486			2e-19	Tier 4: intronic/intergenic
rs574711622	13	73818208	C>T	0	intron_variant	KLF12	3e-15	Tier 4: intronic/intergenic
rs184179564	8	143374709	C>G,T	0.001	intron_variant	RHPN1	5e-13	Tier 4: intronic/intergenic
rs564420311	16	55679239	T>C	0.001	intron_variant	SLC6A2	3e-12	Tier 4: intronic/intergenic
rs184687038	14	69238847	C>G,T	0.001	intron_variant	EXD2	4e-12	Tier 4: intronic/intergenic
rs193021393	11	25501410	C>G,T	0.002	intron_variant	LUZP2 - RPL36AP40	8e-12	Tier 4: intronic/intergenic
rs185095296	7	2613129	C>T	0.003	3_prime_UTR_variant	IQCE	1e-11	Tier 2: splice/UTR
rs112026708	4	31166111	C>A,T	0.001	intergenic_variant	PCDH7 - LINC02497	2e-11	Tier 4: intronic/intergenic
rs192451515	22	22183426	A>G	0.001	intergenic_variant	IGLVV-58 - BMP6P1	2e-11	Tier 4: intronic/intergenic
rs182529943	4	55842819	G>A,C	0.001	intergenic_variant	EXOC1L - EXOC1	2e-11	Tier 4: intronic/intergenic
rs547043053	9	105199097	T>A,C	0.001	non_coding_transcript_exon_variant	RN7SKP191 - SLC44A1	2e-11	Tier 4: intronic/intergenic
rs563018585	18	10251581	G>A,C	0.001	intergenic_variant	VAPA - LINC01254	3e-11	Tier 4: intronic/intergenic
rs185811454	7	125528203	T>A	0	intergenic_variant	POT1-AS1 - GRM8	4e-11	Tier 4: intronic/intergenic
rs7237205	18	35927177	T>A,C,G	0.05	intron_variant	MIR187 - MIR3929	7e-09	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
279726	NM_021098.3(CACNA1H):c.5809G>A (p.Val1937Met)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
783259	NM_021098.3(CACNA1H):c.4714C>T (p.Arg1572Trp)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1H	Orphanet:642671	Familial hyperaldosteronism type IV
CACNA1H	Orphanet:64280	Childhood absence epilepsy

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
CACNA1H	HGNC:1395	ENSG00000196557	O95180	Voltage-dependent T-type calcium channel subunit alpha-1H	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1H	Voltage-dependent T-type calcium channel subunit alpha-1H	Voltage-sensitive calcium channel that gives rise to T-type calcium currents.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1H	Ion channel	yes		VDCC_T_a1, Ion_trans_dom, Volt_channel_dom_sf

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
lower esophagus	1
lower esophagus muscularis layer	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1H	166	broad	marker	lower esophagus muscularis layer, muscle layer of sigmoid colon, lower esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1H	1,564

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1H	O95180	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.008	CACNA1H
NCAM signaling for neurite out-growth	1	271.9×	0.008	CACNA1H
Smooth Muscle Contraction	1	265.6×	0.008	CACNA1H
Cellular responses to mechanical stimuli	1	259.6×	0.008	CACNA1H
NCAM1 interactions	1	248.3×	0.008	CACNA1H
Muscle contraction	1	77.2×	0.022	CACNA1H
Axon guidance	1	45.1×	0.029	CACNA1H
Nervous system development	1	42.9×	0.029	CACNA1H
Cellular responses to stimuli	1	31.5×	0.035	CACNA1H
Developmental Biology	1	14.5×	0.069	CACNA1H

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
aldosterone biosynthetic process	1	3370.4×	0.003	CACNA1H
cortisol biosynthetic process	1	2106.5×	0.003	CACNA1H
positive regulation of acrosome reaction	1	1532.0×	0.003	CACNA1H
cellular response to potassium ion	1	1053.2×	0.003	CACNA1H
obsolete inorganic cation transmembrane transport	1	936.2×	0.003	CACNA1H
calcium ion import	1	802.5×	0.003	CACNA1H
myoblast fusion	1	601.9×	0.003	CACNA1H
calcium ion import across plasma membrane	1	543.6×	0.003	CACNA1H
regulation of heart contraction	1	495.6×	0.003	CACNA1H
cellular response to hormone stimulus	1	383.0×	0.003	CACNA1H
regulation of membrane potential	1	230.8×	0.005	CACNA1H
muscle contraction	1	208.1×	0.005	CACNA1H
muscle organ development	1	166.8×	0.006	CACNA1H

Therapeutics

Drugs indicated for this disease

2 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Spironolactone	Approved (phase 4)
Triamterene	Approved (phase 4)
XL550	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Amlodipine, Everolimus, Osilodrostat.

Drug target analysis

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

Druggability breadth: 1 of 1 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
CACNA1H	PIMOZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1H	10	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIMOZIDE	4	CACNA1H
MIBEFRADIL	4	CACNA1H
NIMODIPINE	4	CACNA1H
TACRINE	4	CACNA1H
CILNIDIPINE	3	CACNA1H
SUVECALTAMIDE	2	CACNA1H
FLUNARIZINE	2	CACNA1H
APINOCALTAMIDE	2	CACNA1H
Z160	2	CACNA1H
ULIXACALTAMIDE	1	CACNA1H

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1H	124	Binding:102, Functional:17, ADMET:4, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1H	124

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

10 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)
PIMOZIDE	4	CACNA1H
MIBEFRADIL	4	CACNA1H
NIMODIPINE	4	CACNA1H
TACRINE	4	CACNA1H
CILNIDIPINE	3	CACNA1H
SUVECALTAMIDE	2	CACNA1H
FLUNARIZINE	2	CACNA1H
APINOCALTAMIDE	2	CACNA1H
Z160	2	CACNA1H
ULIXACALTAMIDE	1	CACNA1H

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1H
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 30.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE4	3
PHASE2	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00155064	PHASE4	COMPLETED	Kallikrein-kinin (KKS) and Renin-angiotensin-aldosterone System (RAAS) in Primary Aldosteronism
NCT00451672	PHASE4	UNKNOWN	The Therapeutic Effect of Bromocriptin in Patients With Primary Aldosteronism
NCT00553722	PHASE4	UNKNOWN	Does Aldosterone Cause Hypertension by a Non-Renal Mechanism?
NCT01096654	PHASE3	COMPLETED	SPARTACUS: Subtyping Primary Aldosteronism: a Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan.
NCT06246357	PHASE2	RECRUITING	Evaluating the Functional Status of the Adrenal Glands With [68Ga]Ga-PentixaFor in Hyperaldosteronism and Hypercortisolism
NCT04605549	PHASE2	COMPLETED	A Study of CIN-107 in Adults With Primary Aldosteronism
NCT02832388	Not specified	RECRUITING	Primary Aldosteronism in Western Norway
NCT05925569	Not specified	ACTIVE_NOT_RECRUITING	Electronic Alert to Improve Testing For Primary Aldosteronism in Patients With Hypertension
NCT06192238	Not specified	NOT_YET_RECRUITING	China National Study of Adrenal Venous Sampling
NCT07027254	Not specified	RECRUITING	PETAL Trial: Impact of Gallium-68 Pentixafor PET-CT on Surgical Outcomes in Primary Aldosteronism
NCT07252284	Not specified	RECRUITING	CHina Adrenal Venous saMPling InvestigatiON
NCT07328230	Not specified	RECRUITING	Superselective Adrenal Arterial Embolization Versus Oral Spironolactone for Treatment of Idiopathic Hyperaldosteronism
NCT00001176	Not specified	COMPLETED	Effects of Salt Intake on the Nervous Systems of Patients With Salt-Sensitive High Blood Pressure
NCT00004354	Not specified	COMPLETED	Study of Prevalence and Clinical Phenotype in Patients With Glucocorticoid-Remediable Aldosteronism
NCT00407784	Not specified	UNKNOWN	Diagnostic Properties of Aldosterone-Renin Ratio in Primary Aldosteronism Among Hypertensives.
NCT01234220	Not specified	COMPLETED	Adrenal Vein Sampling International Study (AVIS Study)
NCT01431326	Not specified	COMPLETED	Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care
NCT01897727	Not specified	COMPLETED	Etiology of Sleep Apnea-related Hyperaldosteronism - BP Treatment
NCT02030587	Not specified	UNKNOWN	Laparoscopic Adrenalectomy Versus Radiofrequency Ablation
NCT02751021	Not specified	COMPLETED	Sleep Apnea Diagnosis Using a Novel Pacemaker Algorithm and Link With Aldosterone Plasma Level in Patients Presenting With Diastolic Dysfunction
NCT02938910	Not specified	COMPLETED	Study of Myocardial Interstitial Fibrosis in Hyperaldosteronism
NCT02945904	Not specified	COMPLETED	IS Metomidate PET-CT Superior to Adrenal Venous Sampling in Predicting Outcome From Adrenalectomy in Patients With Primary Hyperaldosteronism
NCT03414918	Not specified	UNKNOWN	Macrolides for KCNJ5 - Mutated Aldosterone-Producing Adenoma (MAPA)
NCT03778645	Not specified	UNKNOWN	Adrenal Venous Sampling Via an Antecubital Approach
NCT04150666	Not specified	WITHDRAWN	The Water Intake Trail and Primary Aldosteronism Postoperation(WIT-PAP)
NCT04328181	Not specified	UNKNOWN	Comparison of Imaging Quality Between Spectral Photon Counting Computed Tomography (SPCCT) and Dual Energy Computed Tomography (DECT)
NCT05826080	Not specified	UNKNOWN	Effect of Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling in Primary Aldosteronism
NCT06008184	Not specified	UNKNOWN	Real-time Monitoring of Cortisol - Comparison of Cortisol Levels in Four Biological Fluids
NCT06029803	Not specified	UNKNOWN	Antecubital Versus Femoral Approach for Adrenal Venous Sampling
NCT06090617	Not specified	UNKNOWN	Water and Electrolytes Content in HYpertension (WHYSKI) in the SKIn

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BROMOCRIPTINE	4	3
EPLERENONE	4	2
SPIRONOLACTONE	4	2
CAPTOPRIL	4	1
CHEMBL1625141	0	1
CHEMBL4206476	0	1
CHEMBL4206925	0	1