Is ARMC5 p.Ala243= (c.729C>T) pathogenic?

ARMC5 p.Ala243= (c.729C>T) is classified Benign/Likely benign in ARMC5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-10-25). Low-frequency (popmax 2.25%, afr); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Ala243= (c.729C>T)?

ARMC5 p.Ala243= (c.729C>T) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Ala243= (c.729C>T) in the general population?

ARMC5 p.Ala243= (c.729C>T) is low-frequency (popmax 2.25%, afr) (gnomAD).

ARMC5 p.Ala243=

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.729C>T · rs114871627 · VCV777011

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.25%, afr)

Conditions

ACTH-independent macronodular adrenal hyperplasia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -2
Overall
CADD	1.274	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.25% African / African-American · 1,690/75,032 alleles

Filtering AF 2.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.13%

Overall 0.119% 1,919/1,609,618 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.25%	44
Remaining individualsnot grpmax-eligible	0.139%	718
Admixed American	0.125%	800
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00534%	18,729
East Asian	0.00223%	44,862
South Asian	0.0022%	45,536

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.Ala243=
Coding: c.729C>T
MANE Select: NM_001105247
dbSNP: rs114871627
Type: single nucleotide variant
Location: chr16:31462276 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 243: 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.Ala243Gly Uncertain significance ★ ⚠ same residue
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ 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-ala243 (accessed [today's date]).

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