ARMC5

Chr 16AD

armadillo repeat containing 5

Also known as: AIMAH2

NCBI Gene: 79798ENSG00000140691UniProt: Q96C12OMIM: 615549

This protein functions as a substrate-recognition component of a BCR E3 ubiquitin ligase complex that regulates RNA polymerase II transcription termination and controls steroidogenesis by modulating steroidogenic enzyme expression and cortisol production. Mutations cause ACTH-independent macronodular adrenal hyperplasia, a condition affecting adrenal gland growth and steroid hormone production. The inheritance pattern is autosomal dominant, and the gene shows high constraint against loss-of-function variants (LOEUF 0.491).

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.491 OMIM phenotype
Clinical Summary— ARMC5
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
39 unique Pathogenic / Likely Pathogenic· 182 VUS of 330 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — ARMC5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
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
1.71Z-score
OE missense 0.80 (0.74–0.87)
476 obs / 593.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.26 (0.15–0.49)
0≤0.351.4
Missense OE0.80 (0.74–0.87)
0≤0.61.4
Synonymous OE1.17
0≤1.21.6
LoF obs/exp: 7 / 26.8Missense obs/exp: 476 / 593.1Syn Z: -2.21
DN
0.4983th %ile
GOF
0.7126th %ile
LOF
0.3941th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 59% of P/LP variants are LoF · LOEUF 0.49
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.PMID:32901291

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

330 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic15
VUS182
Likely Benign72
Benign21
Conflicting6
24
Pathogenic
15
Likely Pathogenic
182
VUS
72
Likely Benign
21
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
3
7
0
24
Likely Pathogenic
9
5
1
0
15
VUS
6
168
7
1
182
Likely Benign
0
18
1
53
72
Benign
0
7
1
13
21
Conflicting
—6
Total292011767320

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search 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
2026Open Access
Primary Bilateral Macronodular Adrenal Hyperplasia Associated With ARMC5 Variant and Pituitary Microadenoma.
O'Connor-Ramiro L et al.·JCEM Case Rep
2026Open Access
Bilateral Adrenalectomy for Primary Bilateral Macronodular Adrenocortical Hyperplasia With a Novel ARMC5 Mutation Site.
Yu CG et al.·J Clin Med Res
2025Open Access
A Novel ARMC5 Germline Variant in Siblings With Primary Bilateral Macronodular Adrenal Hyperplasia and Colonic Adenomas.
Handa T et al.·JCEM Case Rep
2025Open 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
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients