Is ARC p.Arg392Gln (c.1175G>A) pathogenic?

ARC p.Arg392Gln (c.1175G>A) is classified Uncertain significance in ARC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0764); Ultra-rare (popmax 0.0318%, sas).

How common is ARC p.Arg392Gln (c.1175G>A) in the general population?

ARC p.Arg392Gln (c.1175G>A) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about ARC p.Arg392Gln (c.1175G>A)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

ARC p.Arg392Gln

c.1175G>A · VCV3888148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.95	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 1.3	GERP -2.1, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 118 bp · p 0.1 · regional, not allelic
Overall
CADD	14.85	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0318% South Asian · 26/81,750 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.00252% 39/1,545,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0318%	3,144
Ashkenazi Jewishnot grpmax-eligible	0.00386%	25,940
European (non-Finnish)	0.00105%	95,557

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: ARC
Protein: p.Arg392Gln
Coding: c.1175G>A
MANE Select: NM_015193
Type: single nucleotide variant
Location: chr8:142613097 (GRCh38)
Gene constraint: LOEUF 1.393 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.72 · 11 PDB
Residue 392: the 'disordered' region

Full ARC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARC c.*258C>T Benign ★★ same type
ARC p.Ala144Ser Uncertain significance ★ ⚠ same type
ARC p.Arg107Cys Uncertain significance ★ ⚠ same type
ARC p.Arg129His Uncertain significance ★ ⚠ same type
ARC p.Arg304His Uncertain significance ★ ⚠ same type
ARC p.Arg335Cys Uncertain significance ★ ⚠ same type
ARC p.Asp307Glu Uncertain significance ★ ⚠ same type
ARC p.Asp374Asn Uncertain significance ★ ⚠ same type

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/arc-p-arg392gln (accessed [today's date]).

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