Is ADRB3 p.Lys151Arg (c.452A>G) pathogenic?

ADRB3 p.Lys151Arg (c.452A>G) is classified Uncertain significance in ADRB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0809); Ultra-rare (popmax 0.0496%, mid); Associated with obesity disorder.

What condition is associated with ADRB3 p.Lys151Arg (c.452A>G)?

ADRB3 p.Lys151Arg (c.452A>G) is associated with obesity disorder (ClinVar).

How common is ADRB3 p.Lys151Arg (c.452A>G) in the general population?

ADRB3 p.Lys151Arg (c.452A>G) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about ADRB3 p.Lys151Arg (c.452A>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

ADRB3 p.Lys151Arg

c.452A>G · rs200133226 · VCV1050272

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

obesity disorder

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -3.50	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 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	22.6	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 0.0496% Middle Eastern · 3/6,046 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0126%

Overall 0.0183% 288/1,578,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.249%	401
Middle Easterngrpmax	0.0496%	2,015
Remaining individualsnot grpmax-eligible	0.036%	2,780
Admixed American	0.0223%	4,494
European (non-Finnish)	0.0152%	6,564
South Asian	0.00231%	43,326

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: ADRB3
Protein: p.Lys151Arg
Coding: c.452A>G
MANE Select: NM_000025
dbSNP: rs200133226
Type: single nucleotide variant
Location: chr8:37966018 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41 · 2 PDB
Residue 151: a disulfide bond; an α-helix

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

Disease context

obesity disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADRB3 p.Asn338Ser Uncertain significance ★★ ⚠ same condition
ADRB3 p.Trp64Arg Benign ★★ same condition
ADRB3 c.1205+14G>T Benign ★★ same type
ADRB3 c.1206-96A>G Benign ★★ same type
ADRB3 c.*250G>C Benign ★★ same type
ADRB3 p.Arg353Cys Benign ★★ ⚠ same type
ADRB3 p.Ala130Thr Uncertain significance ★ ⚠ same type
ADRB3 p.Ala132Asp 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/adrb3-p-lys151arg (accessed [today's date]).

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