Is ARMC5 p.Val114fs (c.337_338dup) pathogenic?

ARMC5 p.Val114fs (c.337338dup) is classified Pathogenic in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-30). Very rare (popmax 0.00017%, nfe); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Val114fs (c.337_338dup)?

ARMC5 p.Val114fs (c.337_338dup) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Val114fs (c.337_338dup) in the general population?

ARMC5 p.Val114fs (c.337_338dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

ARMC5 p.Val114fs

Q: How is Cushing syndrome due to bilateral macronodular adrenocortical disease inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.337_338dup · rs2544851883 · VCV1803110

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

ACTH-independent macronodular adrenal hyperplasia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.5	GERP 1.1, phastCons 0.033

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,446,666 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ARMC5
Protein: p.Val114fs
Coding: c.337_338dup
MANE Select: NM_001105247
dbSNP: rs2544851883
Type: Duplication
Location: chr16:31459859 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 114: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2); the 'disordered' region

Full ARMC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTH-independent macronodular adrenal hyperplasia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cushing syndrome due to bilateral macronodular adrenocortical disease (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: All ages
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ARMC5 p.Ala409fs Pathogenic ★ same condition
ARMC5 p.Val114= Likely benign ★ same residue
ARMC5 p.Glu59fs Pathogenic same condition
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ same condition
ARMC5 p.Ala243= Benign/Likely benign ★★ same condition
ARMC5 p.Leu156Phe Benign/Likely benign ★★ same condition
ARMC5 p.Arg267Ter Pathogenic ★ same condition
ARMC5 p.Arg315Trp Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/armc5-p-val114fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown