Is ADRB3 p.Ala231Val (c.692C>T) pathogenic?

ADRB3 p.Ala231Val (c.692C>T) is classified Uncertain significance in ADRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.3259); Ultra-rare (popmax 0.0392%, amr).

How common is ADRB3 p.Ala231Val (c.692C>T) in the general population?

ADRB3 p.Ala231Val (c.692C>T) is ultra-rare (popmax 0.0392%, amr) (gnomAD).

What do computational predictors say about ADRB3 p.Ala231Val (c.692C>T)?

AlphaMissense predicts likely benign (score 0.3259) — an in-silico prediction, not a clinical call.

ADRB3 p.Ala231Val

c.692C>T · rs555759809 · VCV2354689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3259 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3259	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	31.0	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 0.0392% Admixed American · 20/51,008 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.00297% 46/1,551,410 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0392%	2,550
Remaining individualsnot grpmax-eligible	0.00998%	10,020
European (non-Finnish)	0.00174%	57,344

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: ADRB3
Protein: p.Ala231Val
Coding: c.692C>T
MANE Select: NM_000025
dbSNP: rs555759809
Type: single nucleotide variant
Location: chr8:37965778 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41 · 2 PDB
Residue 231: an α-helix

Full ADRB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/adrb3-p-ala231val (accessed [today's date]).

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