Is ARMC5 p.Ile515fs (c.1533_1576del) pathogenic?

ARMC5 p.Ile515fs (c.15331576del) is classified Likely pathogenic in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Ile515fs (c.1533_1576del)?

ARMC5 p.Ile515fs (c.1533_1576del) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

ARMC5 p.Ile515fs

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.1533_1576del · VCV4855556

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 4 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.2	GERP -0.36, phastCons 1

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

Variant & gene context

Gene: ARMC5
Protein: p.Ile515fs
Coding: c.1533_1576del
MANE Select: NM_001105247
Type: Deletion
Location: chr16:31464550 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 515: the 'disordered' region; a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2)

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.Leu373fs Likely pathogenic ★ same condition
ARMC5 c.1864+200del Uncertain significance ★ same condition
ARMC5 p.Ile515Met Uncertain significance ★ ⚠ same residue
ARMC5 p.Cys813fs Pathogenic same condition
ARMC5 p.Gly57fs Pathogenic same condition
ARMC5 p.Leu676fs Pathogenic same condition
ARMC5 p.Ser95fs Pathogenic same condition
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ 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-ile515fs (accessed [today's date]).

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