Is ARMC5 p.Arg764Ter (c.2290C>T) pathogenic?

ARMC5 p.Arg764Ter (c.2290C>T) is classified Pathogenic in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-27). Very rare (popmax 0.000254%, nfe); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Arg764Ter (c.2290C>T)?

ARMC5 p.Arg764Ter (c.2290C>T) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Arg764Ter (c.2290C>T) in the general population?

ARMC5 p.Arg764Ter (c.2290C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

ARMC5 p.Arg764Ter

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.2290C>T · rs778422149 · VCV1323417

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, 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	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.71, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,852 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,612 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.Arg764Ter
Coding: c.2290C>T
MANE Select: NM_001105247
dbSNP: rs778422149
Type: single nucleotide variant
Location: chr16:31466371 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 764: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2); the btb domain

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.Arg764Gln Uncertain significance ★ ⚠ same residue
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.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-arg764ter (accessed [today's date]).

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