Is ARMC5 p.Pro731Arg (c.2192C>G) pathogenic?

ARMC5 p.Pro731Arg (c.2192C>G) is classified Conflicting classifications of pathogenicity in ARMC5 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.0938); Rare (popmax 0.973%, mid); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Pro731Arg (c.2192C>G)?

ARMC5 p.Pro731Arg (c.2192C>G) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Pro731Arg (c.2192C>G) in the general population?

ARMC5 p.Pro731Arg (c.2192C>G) is rare (popmax 0.973%, mid) (gnomAD).

What do computational predictors say about ARMC5 p.Pro731Arg (c.2192C>G)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

ARMC5 p.Pro731Arg

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.2192C>G · rs200951744 · VCV1303338

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.973%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTH-independent macronodular adrenal hyperplasia 2

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.7, phastCons 0.011
Regional constraint	o/e 0.80	unconstrained · MANE · 4,961 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	18.39	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.973% Middle Eastern · 59/6,062 alleles

Filtering AF 0.775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.703%

Overall 0.122% 1,964/1,613,934 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.973%	103
Ashkenazi Jewishnot grpmax-eligible	0.75%	133
Admixed American	0.323%	309
African / African-American	0.272%	368
Remaining individualsnot grpmax-eligible	0.245%	408
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)	0.0948%	1,055
South Asian	0.00988%	10,121
Finnishnot grpmax-eligible	0.00313%	31,966
East Asian	0.00223%	44,876

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.Pro731Arg
Coding: c.2192C>G
MANE Select: NM_001105247
dbSNP: rs200951744
Type: single nucleotide variant
Location: chr16:31466273 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 731: 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-pro731arg (accessed [today's date]).

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