Is ARC p.Pro383Ala (c.1147C>G) pathogenic?

ARC p.Pro383Ala (c.1147C>G) is classified Uncertain significance in ARC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely benign (0.0577); Ultra-rare (popmax 0.0553%, amr).

How common is ARC p.Pro383Ala (c.1147C>G) in the general population?

ARC p.Pro383Ala (c.1147C>G) is ultra-rare (popmax 0.0553%, amr) (gnomAD).

What do computational predictors say about ARC p.Pro383Ala (c.1147C>G)?

AlphaMissense predicts likely benign (score 0.0577) — an in-silico prediction, not a clinical call.

ARC p.Pro383Ala

c.1147C>G · rs750521419 · VCV3128295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0553%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0577	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 118 bp · p 0.1 · regional, not allelic
Overall
CADD	18.24	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 0.0553% Admixed American · 32/57,832 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00202% 32/1,580,504 alleles · ultra-rare exomes 30/1,428,344 · genomes 2/152,160 · joint denominator

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.Pro383Ala
Coding: c.1147C>G
MANE Select: NM_015193
dbSNP: rs750521419
Type: single nucleotide variant
Location: chr8:142613125 (GRCh38)
Gene constraint: LOEUF 1.393 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.72 · 11 PDB
Residue 383: 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.Arg392Gln Uncertain significance ★ ⚠ same type
ARC p.Asp307Glu 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-pro383ala (accessed [today's date]).

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