Is ARC p.Arg129His (c.386G>A) pathogenic?

ARC p.Arg129His (c.386G>A) is classified Uncertain significance in ARC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.2265); Very rare (popmax 0.00538%, amr).

How common is ARC p.Arg129His (c.386G>A) in the general population?

ARC p.Arg129His (c.386G>A) is very rare (popmax 0.00538%, amr) (gnomAD).

What do computational predictors say about ARC p.Arg129His (c.386G>A)?

AlphaMissense predicts likely benign (score 0.2265) — an in-silico prediction, not a clinical call.

ARC p.Arg129His

c.386G>A · VCV3309837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2265	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -2.18	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 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 618 bp · p 0.035 · regional, not allelic
Overall
CADD	29.2	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 0.00538% Admixed American · 3/55,768 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000696%

Overall 0.000254% 4/1,572,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00538%	18,589
East Asian	0.00234%	42,814

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.Arg129His
Coding: c.386G>A
MANE Select: NM_015193
Type: single nucleotide variant
Location: chr8:142613886 (GRCh38)
Gene constraint: LOEUF 1.393 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.72 · 11 PDB
Residue 129: an α-helix

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.Arg304His Uncertain significance ★ ⚠ same type
ARC p.Arg335Cys Uncertain significance ★ ⚠ same type
ARC p.Arg392Gln 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-arg129his (accessed [today's date]).

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