ARMC5

Chr 16

armadillo repeat containing 5

Also known as: AIMAH2

NCBI Gene: 79798 ENSG00000140691 UniProt: Q96C12

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).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.49

Clinical Summary— ARMC5

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

32 unique Pathogenic / Likely Pathogenic· 176 VUS of 317 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ARMC5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.26 (0.15–0.49)

0≤0.351.4

Missense OE?0.80 (0.74–0.87)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 7 / 26.8Missense obs/exp: 476 / 593.1Syn Z: -2.21

This gene — mechanism propensity

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 · 75% 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.1

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

References

1.PMID 32901291 ↗

ClinVar Variant Classifications

317 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic15

VUS176

Likely Benign72

Benign21

Conflicting6

Pathogenic

Likely Pathogenic

176

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	3	0	0	17
Likely Pathogenic	10	5	0	0	15
VUS	6	168	1	1	176
Likely Benign	0	18	1	53	72
Benign	0	7	1	13	21
Conflicting	—				6
Total	30	201	3	67	307

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap ARMC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →