ARMC5

Chr 16

armadillo repeat containing 5

Also known as: AIMAH2

NCBI Gene: 79798ENSG00000140691UniProt: Q96C12

This gene encodes a member of the ARM (armadillo/beta-catenin-like repeat) superfamily. The ARM repeat is a tandemly repeated sequence motif with approximately 40 amino acid long. This repeat is implicated in mediating protein-protein interactions. The encoded protein contains seven ARM repeats. Mutations in this gene are associated with primary bilateral macronodular adrenal hyperplasia, which is also known as ACTH-independent macronodular adrenal hyperplasia 2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

Primary Disease Associations & Inheritance

UniProtACTH-independent macronodular adrenal hyperplasia 2
314
ClinVar variants
38
Pathogenic / LP
0.11
pLI score
0
Active trials
Clinical Summary— ARMC5
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 179 VUS of 314 total submissions
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.49LOEUF
pLI 0.108
Z-score 3.54
OE 0.26 (0.15–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.71Z-score
OE missense 0.80 (0.74–0.87)
476 obs / 593.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.15–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.74–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17
0≤1.21.6
LoF obs/exp: 7 / 26.8Missense obs/exp: 476 / 593.1Syn Z: -2.21

ClinVar Variant Classifications

314 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic14
VUS179
Likely Benign70
Benign21
Conflicting6
24
Pathogenic
14
Likely Pathogenic
179
VUS
70
Likely Benign
21
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
3
12
0
24
Likely Pathogenic
5
5
4
0
14
VUS
4
166
8
1
179
Likely Benign
0
17
1
52
70
Benign
0
7
1
13
21
Conflicting
—6
Total181982666314

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ARMC5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — ARMC5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia.
Bertherat J et al.·Endocr Rev
2023
Morphological Harbingers of ARMC5-Pathogenic Variant-Related Bilateral Macronodular Adrenocortical Disease.
de Arruda Botelho MLA et al.·Endocr Pathol
2023
The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update.
Bouys L et al.·Orphanet J Rare Dis
2025Review
Advancements in the research of the structure, function, and disease-related roles of ARMC5.
Qu Y et al.·Front Med
2025Review
The molecular genetics of adrenal cushing.
Vaduva P et al.·Hormones (Athens)
2024Review
Genetics of primary hyperaldosteronism.
Dutta RK et al.·Endocr Relat Cancer
2016Review
The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review.
Sun J et al.·Front Endocrinol (Lausanne)
2024Review
Genomics of benign adrenocortical tumors.
Jouinot A et al.·J Steroid Biochem Mol Biol
2019Review
ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.
Espiard S et al.·J Clin Endocrinol Metab
2015Cohort
Primary Aldosteronism and ARMC5 Variants.
Zilbermint M et al.·J Clin Endocrinol Metab
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Primary Bilateral Macronodular Adrenocortical Disease With Concomitant Cushing Syndrome and Primary Aldosteronism Harboring Distinct ARMC5 Mutations in Individual Nodules.
Kitazawa S et al.·Cureus
2026🔓 Open Access
Primary Bilateral Macronodular Adrenal Hyperplasia Associated With ARMC5 Variant and Pituitary Microadenoma.
O'Connor-Ramiro L et al.·JCEM Case Rep
2026🔓 Open Access
Bilateral Adrenalectomy for Primary Bilateral Macronodular Adrenocortical Hyperplasia With a Novel ARMC5 Mutation Site.
Yu CG et al.·J Clin Med Res
2025🔓 Open Access
A Novel ARMC5 Germline Variant in Siblings With Primary Bilateral Macronodular Adrenal Hyperplasia and Colonic Adenomas.
Handa T et al.·JCEM Case Rep
2025🔓 Open Access
Nodule density on CT-scan correlates with CYP11B1 expression in a patient with ARMC5 mutated primary bilateral macronodular adrenal hyperplasia.
Wang F et al.·Diagn Pathol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools