Is ARR3 p.Ile217Val (c.649A>G) pathogenic?

ARR3 p.Ile217Val (c.649A>G) is classified Likely benign in ARR3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.0829); Ultra-rare (popmax 0.0256%, nfe).

How common is ARR3 p.Ile217Val (c.649A>G) in the general population?

ARR3 p.Ile217Val (c.649A>G) is ultra-rare (popmax 0.0256%, nfe) (gnomAD).

What do computational predictors say about ARR3 p.Ile217Val (c.649A>G)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

ARR3 p.Ile217Val

c.649A>G · rs138489730 · VCV2660808

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0256%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -4.63	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 0.84	GERP -4.5, phastCons 0.028
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	13.38	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 0.0256% European (non-Finnish) · 229/894,608 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.029% 350/1,208,709 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.354%	282
Remaining individualsnot grpmax-eligible	0.0631%	1,585
European (non-Finnish)grpmax	0.0256%	3,907
Middle Eastern	0.0229%	4,372
Finnishnot grpmax-eligible	0.015%	6,645
African / African-American	0.00527%	18,972
Admixed American	0.00437%	22,878

Ashkenazi Jewish 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: ARR3
Protein: p.Ile217Val
Coding: c.649A>G
MANE Select: NM_004312
dbSNP: rs138489730
Type: single nucleotide variant
Location: chrX:70277755 (GRCh38)
Structure: AlphaFold pLDDT 87.37
Residue 217: 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 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
ARR3 p.Ile365= 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-ile217val (accessed [today's date]).

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