Is ARR3 p.Pro351Arg (c.1052C>G) pathogenic?

ARR3 p.Pro351Arg (c.1052C>G) is classified Likely benign in ARR3 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.173); Rare (popmax 0.209%, nfe).

How common is ARR3 p.Pro351Arg (c.1052C>G) in the general population?

ARR3 p.Pro351Arg (c.1052C>G) is rare (popmax 0.209%, nfe) (gnomAD).

What do computational predictors say about ARR3 p.Pro351Arg (c.1052C>G)?

AlphaMissense predicts likely benign (score 0.173) — an in-silico prediction, not a clinical call.

ARR3 p.Pro351Arg

c.1052C>G · VCV3352517

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.173 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.209%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.173	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -13.16	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	24.0	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 0.209% European (non-Finnish) · 1,873/894,993 alleles

Filtering AF 0.201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.177% 2,146/1,209,147 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.209%	478
Finnishnot grpmax-eligible	0.208%	480
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
Remaining individualsnot grpmax-eligible	0.139%	721
South Asian	0.0741%	1,350
Admixed American	0.0723%	1,384
Middle Eastern	0.0231%	4,333
African / African-American	0.00352%	28,441

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: ARR3
Protein: p.Pro351Arg
Coding: c.1052C>G
MANE Select: NM_004312
Type: single nucleotide variant
Location: chrX:70280804 (GRCh38)
Structure: AlphaFold pLDDT 87.37
Residue 351: a UniProt-annotated variant site (in myp26; uncertain significance)

Full ARR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARR3 p.Pro351Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ARR3 c.767+1G>A Pathogenic/Likely pathogenic ★★ same type
ARR3 p.Arg72Ter Pathogenic/Likely pathogenic ★★ same type
ARR3 p.Val82Met Uncertain significance ★★ ⚠ same type
ARR3 c.346-4C>T Benign/Likely benign ★★ same type
ARR3 p.Arg282Gln Likely benign ★★ ⚠ same type
ARR3 p.His205= Likely benign ★★ same type
ARR3 p.His207= Benign/Likely benign ★★ 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/arr3-p-pro351arg (accessed [today's date]).

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