Is ARRB2 p.Val367Ile (c.1099G>A) pathogenic?

ARRB2 p.Val367Ile (c.1099G>A) is classified Uncertain significance in ARRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.00114%, sas).

How common is ARRB2 p.Val367Ile (c.1099G>A) in the general population?

ARRB2 p.Val367Ile (c.1099G>A) is very rare (popmax 0.00114%, sas) (gnomAD).

What do computational predictors say about ARRB2 p.Val367Ile (c.1099G>A)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

ARRB2 p.Val367Ile

c.1099G>A · rs1363085873 · VCV2528030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.97	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 5.7	GERP -0.72, phastCons 0.99
Regional constraint	o/e 0.70	unconstrained · MANE · 10 kb · p 5.2e-12 · regional, not allelic
Overall
CADD	18.43	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 0.00114% South Asian · 1/87,688 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000209% 3/1,437,122 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00114%	87,688
European (non-Finnish)	0.000171%	583,983

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: ARRB2
Protein: p.Val367Ile
Coding: c.1099G>A
MANE Select: NM_004313
dbSNP: rs1363085873
Type: single nucleotide variant
Location: chr17:4720603 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 83.97 · 1 PDB
Residue 367: the 'interaction with traf6' region; the 'interaction with ap2b1' region

Full ARRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRB2 p.Ile82= Benign ★★ same type
ARRB2 p.Leu288= Benign ★★ same type
ARRB2 p.Ala362Thr Uncertain significance ★ ⚠ same type
ARRB2 p.Arg100Cys Uncertain significance ★ ⚠ same type
ARRB2 p.Arg148Gln Uncertain significance ★ ⚠ same type
ARRB2 p.Arg189Cys Uncertain significance ★ ⚠ same type
ARRB2 p.Arg196Gln Uncertain significance ★ ⚠ same type
ARRB2 p.Arg26Gln 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/arrb2-p-val367ile (accessed [today's date]).

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