Is ARMC5 p.Ala47Val (c.140C>T) pathogenic?

ARMC5 p.Ala47Val (c.140C>T) is classified Uncertain significance in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). Ultra-rare (popmax 0.0262%, sas); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Ala47Val (c.140C>T)?

ARMC5 p.Ala47Val (c.140C>T) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Ala47Val (c.140C>T) in the general population?

ARMC5 p.Ala47Val (c.140C>T) is ultra-rare (popmax 0.0262%, sas) (gnomAD).

ARMC5 p.Ala47Val

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.140C>T · VCV3780040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, sas)

Conditions

ACTH-independent macronodular adrenal hyperplasia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.025	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.9
Overall
CADD	1.393	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0262% South Asian · 22/84,068 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00541% 83/1,535,532 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0262%	3,821
Remaining individualsnot grpmax-eligible	0.00834%	11,996
European (non-Finnish)	0.00488%	20,479

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.Ala47Val
Coding: c.140C>T
MANE Select: NM_001105247 · reported on NM_001288767
Type: single nucleotide variant
Location: chr16:31458888 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 47: 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.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
ARMC5 p.Arg364Ter Pathogenic ★ same condition
ARMC5 p.Arg764Ter Pathogenic ★ same condition
ARMC5 p.Glu833Ter 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-ala47val (accessed [today's date]).

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