Is ARMC5 p.Arg315Trp (c.943C>T) pathogenic?

ARMC5 p.Arg315Trp (c.943C>T) is classified Likely pathogenic in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). AlphaMissense: likely pathogenic (0.9562); Very rare (popmax 0.00017%, nfe); Associated with ACTH-independent macronodular adrenal hyperplasia 2.

What condition is associated with ARMC5 p.Arg315Trp (c.943C>T)?

ARMC5 p.Arg315Trp (c.943C>T) is associated with ACTH-independent macronodular adrenal hyperplasia 2 (ClinVar).

How common is ARMC5 p.Arg315Trp (c.943C>T) in the general population?

ARMC5 p.Arg315Trp (c.943C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ARMC5 p.Arg315Trp (c.943C>T)?

AlphaMissense predicts likely pathogenic (score 0.9562) — an in-silico prediction, not a clinical call.

ARMC5 p.Arg315Trp

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.943C>T · VCV3602762

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTH-independent macronodular adrenal hyperplasia 2

Computational evidence

Protein change
AlphaMissense	0.9562	likely pathogenic ✓ concordant with ClinVar · top 7% in ARMC5
REVEL	0.703	pathogenic-leaning
SaProt	LLR -13.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,961 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	24.4	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 0.00017% European (non-Finnish) · 2/1,179,818 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000343% 5/1,459,654 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00483%	20,702
European (non-Finnish)grpmax	0.00017%	589,908

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg315Trp
Coding: c.943C>T
MANE Select: NM_001105247
Type: single nucleotide variant
Location: chr16:31462490 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 315: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2); a UniProt-annotated variant site (in aimah2; loss of function in promoting apoptosis; decreased association with polr2a component of rna polymerase ii; reduced ability to promote degradation of srebf1)

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.Arg315Pro Likely pathogenic ★ 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.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-arg315trp (accessed [today's date]).

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