ACTH-independent macronodular adrenal hyperplasia 2

Summary

ACTH-independent macronodular adrenal hyperplasia 2 (MONDO:0014416) is a disease caused by ARMC5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ARMC5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTH-independent macronodular adrenal hyperplasia 2
Mondo ID	MONDO:0014416
OMIM	615954
DOID	DOID:0111624
UMLS	C4014803
MedGen	863240
GARD	0016034
Is cancer (heuristic)	no

Also known as: ACTH-independent macronodular adrenal hyperplasia 2 · ACTH-independent macronodular adrenal hyperplasia 2, autosomal dominant, somatic mutation · ACTH-independent macronodular adrenal hyperplasia type 2 · AIMAH2 · ARMC5 Cushing syndrome due to macronodular adrenal hyperplasia · Cushing syndrome due to macronodular adrenal hyperplasia caused by mutation in ARMC5 · primary macronodular adrenal hyperplasia

Data availability: 39 ClinVar variants · 3 GenCC gene-disease records.

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 2

Related subtypes (2): ACTH-independent macronodular adrenal hyperplasia 1, 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

39 retrieved; paginated sample, class counts are floors:

14 pathogenic, 12 uncertain significance, 8 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323417	NM_001105247.2(ARMC5):c.2290C>T (p.Arg764Ter)	ARMC5	Pathogenic	criteria provided, single submitter
1339346	NM_001105247.2(ARMC5):c.174dup (p.Glu59fs)	ARMC5	Pathogenic	no assertion criteria provided
1339347	NM_001105247.2(ARMC5):c.2025del (p.Leu676fs)	ARMC5	Pathogenic	no assertion criteria provided
1341364	NM_001105247.2(ARMC5):c.283_286del (p.Ser95fs)	ARMC5	Pathogenic	no assertion criteria provided
144052	NM_001105247.2(ARMC5):c.799C>T (p.Arg267Ter)	ARMC5	Pathogenic	no assertion criteria provided
144053	NM_001105247.2(ARMC5):c.2692C>T (p.Arg898Trp)	ARMC5	Pathogenic	no assertion criteria provided
144054	NM_001105247.2(ARMC5):c.256C>T (p.Gln86Ter)	ARMC5	Pathogenic	no assertion criteria provided
144055	NM_001105247.2(ARMC5):c.1643T>C (p.Leu548Pro)	ARMC5	Pathogenic	no assertion criteria provided
144056	NM_001105247.2(ARMC5):c.170del (p.Gly57fs)	ARMC5	Pathogenic	no assertion criteria provided
144058	NM_001105247.2(ARMC5):c.1094T>C (p.Leu365Pro)	ARMC5	Pathogenic	no assertion criteria provided
1693528	NM_001105247.2(ARMC5):c.2436del (p.Cys813fs)	ARMC5	Pathogenic	no assertion criteria provided
1803212	NM_001105247.2(ARMC5):c.1199_1224dup (p.Ala409fs)	ARMC5	Pathogenic	criteria provided, single submitter
3048615	NM_001105247.2(ARMC5):c.1090C>T (p.Arg364Ter)	ARMC5	Pathogenic	criteria provided, single submitter
1803110	NM_001105247.2(ARMC5):c.337_338dup (p.Val114fs)	LOC130058906	Pathogenic	criteria provided, single submitter
1339342	NM_001105247.2(ARMC5):c.968G>A (p.Gly323Asp)	ARMC5	Likely pathogenic	no assertion criteria provided
1339343	NM_001105247.2(ARMC5):c.1787T>G (p.Leu596Arg)	ARMC5	Likely pathogenic	no assertion criteria provided
1339344	NM_001105247.2(ARMC5):c.2432G>C (p.Arg811Pro)	ARMC5	Likely pathogenic	no assertion criteria provided
3580272	NM_001105247.2(ARMC5):c.1197T>G (p.Tyr399Ter)	ARMC5	Likely pathogenic	criteria provided, single submitter
3580273	NM_001105247.2(ARMC5):c.2497G>T (p.Glu833Ter)	ARMC5	Likely pathogenic	criteria provided, single submitter
3602762	NM_001105247.2(ARMC5):c.943C>T (p.Arg315Trp)	ARMC5	Likely pathogenic	criteria provided, single submitter
4823901	NM_001105247.2(ARMC5):c.1118del (p.Leu373fs)	ARMC5	Likely pathogenic	criteria provided, single submitter
666958	NM_001105247.2(ARMC5):c.1767_1771dup (p.Leu591fs)	ARMC5	Likely pathogenic	criteria provided, single submitter
1303338	NM_001105247.2(ARMC5):c.2192C>G (p.Pro731Arg)	ARMC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633679	NM_001105247.2(ARMC5):c.1084C>T (p.Arg362Trp)	ARMC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032625	NM_001105247.2(ARMC5):c.1864+198T>A	ARMC5	Uncertain significance	criteria provided, single submitter
1032626	NM_001105247.2(ARMC5):c.2657G>A (p.Arg886His)	ARMC5	Uncertain significance	criteria provided, single submitter
144057	NM_001105247.2(ARMC5):c.1777C>T (p.Arg593Trp)	ARMC5	Uncertain significance	criteria provided, single submitter
2366523	NM_001105247.2(ARMC5):c.2403G>T (p.Trp801Cys)	ARMC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439206	NM_001105247.2(ARMC5):c.1000C>T (p.Arg334Cys)	ARMC5	Uncertain significance	criteria provided, single submitter
3067867	NM_001105247.2(ARMC5):c.583G>C (p.Gly195Arg)	ARMC5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ARMC5	Definitive	Autosomal dominant	ACTH-independent macronodular adrenal hyperplasia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARMC5	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease

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
ARMC5	HGNC:25781	ENSG00000140691	Q96C12	Armadillo repeat-containing protein 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARMC5	Armadillo repeat-containing protein 5	Substrate-recognition component of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes.

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)
ARMC5	Other/Unknown	no		BTB/POZ_dom, Armadillo, SKP1/BTB/POZ_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
pancreatic ductal cell	1
tendon of biceps brachii	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARMC5	246	ubiquitous	marker	pancreatic ductal cell, tendon of biceps brachii, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARMC5	701

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARMC5	Q96C12	81.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
adrenal cortex development	1	16852.0×	6e-04	ARMC5
CD4-positive, alpha-beta T cell differentiation	1	2808.7×	0.002	ARMC5
regulation of steroid biosynthetic process	1	1532.0×	0.002	ARMC5
RNA polymerase II transcription initiation surveillance	1	887.0×	0.003	ARMC5
mesoderm formation	1	495.6×	0.004	ARMC5
T cell proliferation	1	383.0×	0.004	ARMC5
anatomical structure morphogenesis	1	139.3×	0.010	ARMC5
in utero embryonic development	1	72.0×	0.016	ARMC5
defense response to virus	1	69.3×	0.016	ARMC5
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	ARMC5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARMC5	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	ARMC5

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)
ARMC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.