Aldosterone-producing adrenal cortex adenoma

Summary

Aldosterone-producing adrenal cortex adenoma (MONDO:0016505) is a cancer with 2 cohort genes (4 GWAS associations across 2 studies; 2 CIViC-evidence somatic drivers; 6 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• GWAS associations: 4
• ClinVar variants: 6
• Phenotypes (HPO): 18

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0100631	Neoplasm of the adrenal gland	Obligate (100%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0003118	Increased circulating cortisol level	Very frequent (80-99%)
HP:0003351	Decreased circulating renin concentration	Very frequent (80-99%)
HP:0011740	Glucocortocoid-insensitive primary hyperaldosteronism	Very frequent (80-99%)
HP:0200114	Metabolic alkalosis	Very frequent (80-99%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0003081	Increased urinary potassium	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0005135	Abnormal T-wave	Frequent (30-79%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aldosterone-producing adrenal cortex adenoma
Mondo ID	MONDO:0016505
EFO	EFO:1000015
Orphanet	231625
NCIT	C48451
UMLS	C1706762
MedGen	353374
GARD	0020621
MedDRA	10056950
Is cancer (heuristic)	yes

Also known as: aldosterone producing adrenal cortex adenoma · aldosterone producing adrenal cortical adenoma · aldosterone-producing adrenal cortex adenoma · APAC · Pure aldosterone-producing adrenocortical carcinoma · Pure aldosterone-secreting adrenocortical carcinoma · Pure APAC

Data availability: 6 ClinVar variants · 4 GWAS associations (2 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism › primary aldosteronism › aldosterone-producing adrenal cortex adenoma

Related subtypes (3): primary unilateral adrenal hyperplasia, ectopic aldosterone-producing tumor, familial hyperaldosteronism

Genetics & variants

GWAS landscape

4 GWAS associations across 2 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2137320	2e-11	LSP1	A	1.56
rs880315	6e-10	CASZ1	C	1.5
rs5905587	6e-08	NDP - RBM39P1	C	1.39
rs661348	1e-06	LSP1	C	1.51

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90129618	Le Floch E	2022	321	0	Identification of risk loci for primary aldosteronism in genome-wide association studies.
GCST90129623	Le Floch E	2022	321	0	Identification of risk loci for primary aldosteronism in genome-wide association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2137320	11	1863112	G>A,C	0.05	intron_variant	LSP1	2e-11	Tier 4: intronic/intergenic
rs880315	1	10736809	T>C,G	0.05	intron_variant	CASZ1	6e-10	Tier 4: intronic/intergenic
rs5905587	X	43974750	T>C,G	0.05	intergenic_variant	NDP - RBM39P1	6e-08	Tier 4: intronic/intergenic
rs661348	11	1884062	T>C	0.05	intron_variant	LSP1	1e-06	Tier 4: intronic/intergenic

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162465	NM_000701.8(ATP1A1):c.299_313del (p.Phe100_Leu104del)	ATP1A1	Pathogenic	no assertion criteria provided
162466	NM_000701.8(ATP1A1):c.311T>G (p.Leu104Arg)	ATP1A1	Pathogenic	no assertion criteria provided
162468	NM_000701.8(ATP1A1):c.995T>G (p.Val332Gly)	ATP1A1	Pathogenic	no assertion criteria provided
162467	NM_001001344.3(ATP2B3):c.1272_1277del (p.Leu425_Val426del)	ATP2B3	Pathogenic	no assertion criteria provided
162469	NM_001001344.3(ATP2B3):c.1273_1278del (p.Leu425_Val426del)	ATP2B3	Pathogenic	no assertion criteria provided
162470	NM_001001344.3(ATP2B3):c.1277_1282del (p.Val426_Val427del)	ATP2B3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
ATP1A1	Act	BRCA
ATP2B3	Act	BRCA

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A1	Orphanet:521414	Autosomal dominant Charcot-Marie-Tooth disease type 2DD
ATP1A1	Orphanet:564178	Primary hypomagnesemia-refractory seizures-intellectual disability syndrome
ATP2B3	Orphanet:314978	X-linked non progressive cerebellar ataxia

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
ATP1A1	HGNC:799	ENSG00000163399	P05023	Sodium/potassium-transporting ATPase subunit alpha-1	clinvar
ATP2B3	HGNC:816	ENSG00000067842	Q16720	Plasma membrane calcium-transporting ATPase 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A1	Sodium/potassium-transporting ATPase subunit alpha-1	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
ATP2B3	Plasma membrane calcium-transporting ATPase 3	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A1	Transcription factor	no	7.2.2.3	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
ATP2B3	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
renal medulla	1
right lobe of thyroid gland	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A1	305	ubiquitous	marker	renal medulla, right lobe of thyroid gland, left lobe of thyroid gland
ATP2B3	145	tissue_specific	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A1	3,520
ATP2B3	3,203

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP1A1	P05023	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2B3	Q16720	74.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Ion transport by P-type ATPases	2	207.6×	2e-04	ATP1A1, ATP2B3
Ion homeostasis	2	203.9×	2e-04	ATP1A1, ATP2B3
Cardiac conduction	2	108.8×	4e-04	ATP1A1, ATP2B3
Ion channel transport	2	96.0×	4e-04	ATP1A1, ATP2B3
Muscle contraction	2	77.2×	5e-04	ATP1A1, ATP2B3
Transport of small molecules	2	25.1×	0.004	ATP1A1, ATP2B3
Reduction of cytosolic Ca++ levels	1	475.8×	0.005	ATP2B3
Platelet calcium homeostasis	1	356.9×	0.005	ATP2B3
Platelet homeostasis	1	139.3×	0.012	ATP2B3
Potential therapeutics for SARS	1	57.1×	0.026	ATP1A1
SARS-CoV Infections	1	27.7×	0.049	ATP1A1
Hemostasis	1	18.0×	0.068	ATP2B3
Viral Infection Pathways	1	15.4×	0.074	ATP1A1
Infectious disease	1	12.4×	0.085	ATP1A1
Disease	1	6.5×	0.147	ATP1A1

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
negative regulation of glucocorticoid biosynthetic process	1	8426.0×	0.003	ATP1A1
positive regulation of striated muscle contraction	1	4213.0×	0.003	ATP1A1
negative regulation of heart contraction	1	2106.5×	0.004	ATP1A1
establishment or maintenance of transmembrane electrochemical gradient	1	1404.3×	0.004	ATP1A1
calcium ion export across plasma membrane	1	1404.3×	0.004	ATP2B3
response to glycoside	1	1203.7×	0.004	ATP1A1
positive regulation of heart contraction	1	1053.2×	0.004	ATP1A1
membrane repolarization during cardiac muscle cell action potential	1	842.6×	0.004	ATP1A1
osmosensory signaling pathway	1	766.0×	0.004	ATP1A1
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.004	ATP1A1
relaxation of cardiac muscle	1	648.1×	0.004	ATP1A1
membrane repolarization	1	648.1×	0.004	ATP1A1
sodium ion export across plasma membrane	1	526.6×	0.004	ATP1A1
cellular response to steroid hormone stimulus	1	526.6×	0.004	ATP1A1
regulation of the force of heart contraction	1	495.6×	0.004	ATP1A1
intracellular potassium ion homeostasis	1	495.6×	0.004	ATP1A1
regulation of sodium ion transport	1	468.1×	0.004	ATP1A1
regulation of cardiac conduction	1	421.3×	0.004	ATP2B3
intracellular sodium ion homeostasis	1	383.0×	0.004	ATP1A1
cardiac muscle cell action potential involved in contraction	1	351.1×	0.004	ATP1A1
regulation of cytosolic calcium ion concentration	1	191.5×	0.007	ATP2B3
potassium ion import across plasma membrane	1	183.2×	0.007	ATP1A1
proton transmembrane transport	1	156.0×	0.008	ATP1A1
regulation of blood pressure	1	110.9×	0.010	ATP1A1
monoatomic ion transmembrane transport	1	104.0×	0.011	ATP2B3
sodium ion transmembrane transport	1	101.5×	0.011	ATP1A1
potassium ion transmembrane transport	1	68.0×	0.015	ATP1A1
response to xenobiotic stimulus	1	34.5×	0.029	ATP1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ATP1A1	DIGOXIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A1	5	4
ATP2B3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIGOXIN	4	ATP1A1
OMEPRAZOLE	4	ATP1A1
DIGITOXIN	4	ATP1A1
LANSOPRAZOLE	4	ATP1A1
ROSTAFUROXIN	2	ATP1A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATP1A1	50	Binding:50

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP1A1	7.2.2.3	P-type Na+ transporter
ATP2B3	7.2.2.10	P-type Ca2+ transporter

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).

Drug repurposing candidates

5 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
DIGOXIN	4	ATP1A1
OMEPRAZOLE	4	ATP1A1
DIGITOXIN	4	ATP1A1
LANSOPRAZOLE	4	ATP1A1
ROSTAFUROXIN	2	ATP1A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP1A1
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	ATP2B3

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)
ATP2B3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.