ACTH-independent macronodular adrenal hyperplasia 1

Summary

ACTH-independent macronodular adrenal hyperplasia 1 (MONDO:0020735) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTH-independent macronodular adrenal hyperplasia 1
Mondo ID	MONDO:0020735
OMIM	219080
DOID	DOID:0111623
UMLS	C1857451
MedGen	347456
GARD	0025230
Is cancer (heuristic)	no

Also known as: ACTH-independent macronodular adrenal hyperplasia · ACTH-independent macronodular adrenal hyperplasia 1 · ACTH-independent macronodular adrenal hyperplasia, Somatic mutation · ACTH-independent macronodular adrenocortical hyperplasia · adrenocorticotropic hormone-independent macronodular adrenal hyperplasia · AIMAH1 · corticotropin-independent macronodular adrenal hyperplasia · Cushing syndrome, adrenal, due to AIMAH

Data availability: 78 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Cushing syndrome due to macronodular adrenal hyperplasia › ACTH-independent macronodular adrenal hyperplasia 1

Related subtypes (2): ACTH-independent macronodular adrenal hyperplasia 2, ACTH-independent macronodular adrenal hyperplasia 3

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

78 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 22 likely benign, 10 benign/likely benign, 6 pathogenic, 6 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1217738	NM_000516.7(GNAS):c.91C>T (p.Gln31Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1455167	NM_000516.7(GNAS):c.1024C>T (p.Arg342Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15933	NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15934	NM_000516.7(GNAS):c.602G>A (p.Arg201His)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15938	NM_000516.7(GNAS):c.565_568del (p.Asp189fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209158	NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3373471	NM_000516.7(GNAS):c.445_446del (p.His149fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587590	NM_000516.7(GNAS):c.970+1G>C	GNAS	Pathogenic	criteria provided, single submitter
3767107	NM_000516.7(GNAS):c.433-2A>C	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531299	NM_000516.7(GNAS):c.585+1G>C	GNAS	Pathogenic	criteria provided, single submitter
816910	NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871093	NM_000516.7(GNAS):c.348dup (p.Val117fs)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1205909	NM_080425.4(GNAS):c.154G>A (p.Glu52Lys)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134492	NM_080425.4(GNAS):c.988A>G (p.Ile330Val)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2963682	NM_000516.7(GNAS):c.585+12C>T	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931358	NM_080425.4(GNAS):c.1276G>C (p.Ala426Pro)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1048823	NM_080425.4(GNAS):c.538C>T (p.Gln180Ter)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098700	NM_080425.4(GNAS):c.1130G>T (p.Gly377Val)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1215279	NM_000516.7(GNAS):c.985G>A (p.Gly329Arg)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1315968	NM_080425.4(GNAS):c.1275C>T (p.Phe425=)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327849	NM_080425.4(GNAS):c.1146C>T (p.Ala382=)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1431017	NM_000516.7(GNAS):c.367G>A (p.Glu123Lys)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
15937	NM_000516.7(GNAS):c.601C>A (p.Arg201Ser)	GNAS	Uncertain significance	criteria provided, single submitter
1686708	NM_000516.7(GNAS):c.683G>A (p.Arg228His)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1952879	NM_000516.7(GNAS):c.230C>T (p.Pro77Leu)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2116501	NM_000516.7(GNAS):c.1121G>A (p.Arg374His)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2230853	NM_080425.4(GNAS):c.1201G>A (p.Asp401Asn)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2634480	NM_000516.7(GNAS):c.529T>A (p.Tyr177Asn)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2694073	NM_000516.7(GNAS):c.695G>A (p.Arg232His)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2820007	NM_000516.7(GNAS):c.278A>G (p.Gln93Arg)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B

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
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	clinvar

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)
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su

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
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAS	410

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
PKA activation in glucagon signalling	1	671.8×	0.006	GNAS
Prostacyclin signalling through prostacyclin receptor	1	601.0×	0.006	GNAS
Glucagon signaling in metabolic regulation	1	346.1×	0.006	GNAS
Glucagon-type ligand receptors	1	346.1×	0.006	GNAS
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.006	GNAS
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.006	GNAS
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.006	GNAS
GPER1 signaling	1	248.3×	0.006	GNAS
G alpha (z) signalling events	1	233.1×	0.006	GNAS
Hedgehog ‘off’ state	1	178.4×	0.007	GNAS
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.007	GNAS
G alpha (s) signalling events	1	73.2×	0.015	GNAS
G alpha (i) signalling events	1	39.0×	0.026	GNAS

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
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	5617.3×	0.002	GNAS
response to parathyroid hormone	1	4213.0×	0.002	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	3370.4×	0.002	GNAS
hair follicle placode formation	1	3370.4×	0.002	GNAS
regulation of skeletal muscle contraction	1	2808.7×	0.002	GNAS
cellular response to catecholamine stimulus	1	2407.4×	0.002	GNAS
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.002	GNAS
intracellular transport	1	1532.0×	0.002	GNAS
response to prostaglandin E	1	1404.3×	0.002	GNAS
adenylate cyclase-activating adrenergic receptor signaling pathway	1	1203.7×	0.002	GNAS
activation of adenylate cyclase activity	1	1123.5×	0.002	GNAS
sensory perception of chemical stimulus	1	1123.5×	0.002	GNAS
negative regulation of multicellular organism growth	1	1123.5×	0.002	GNAS
cellular response to glucagon stimulus	1	842.6×	0.003	GNAS
cellular response to prostaglandin E stimulus	1	842.6×	0.003	GNAS
developmental growth	1	732.7×	0.003	GNAS
cellular response to acidic pH	1	732.7×	0.003	GNAS
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.003	GNAS
negative regulation of inflammatory response to antigenic stimulus	1	601.9×	0.003	GNAS
intracellular glucose homeostasis	1	581.1×	0.003	GNAS
renal water homeostasis	1	510.7×	0.003	GNAS
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	GNAS
platelet aggregation	1	337.0×	0.004	GNAS
cognition	1	285.6×	0.005	GNAS
bone development	1	276.3×	0.005	GNAS
regulation of signal transduction	1	267.5×	0.005	GNAS
protein secretion	1	263.3×	0.005	GNAS
positive regulation of insulin secretion	1	255.3×	0.005	GNAS
female pregnancy	1	210.7×	0.005	GNAS
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	GNAS

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
GNAS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	GNAS

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)
GNAS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.