Is ADRB3 p.Trp64Arg (c.190T>C) pathogenic?

ADRB3 p.Trp64Arg (c.190T>C) is classified Benign in ADRB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-06-09). AlphaMissense: likely benign (0.0519); Common (popmax 18.2%, amr) — too common for a highly-penetrant pathogenic allele; Associated with obesity disorder.

What condition is associated with ADRB3 p.Trp64Arg (c.190T>C)?

ADRB3 p.Trp64Arg (c.190T>C) is associated with obesity disorder (ClinVar).

What do computational predictors say about ADRB3 p.Trp64Arg (c.190T>C)?

AlphaMissense predicts likely benign (score 0.0519) — an in-silico prediction, not a clinical call.

ADRB3 p.Trp64Arg

Q: How common is ADRB3 p.Trp64Arg (c.190T>C) in the general population?

ADRB3 p.Trp64Arg (c.190T>C) is common (popmax 18.2%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.190T>C · rs4994 · VCV17741

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0519 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.2%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

obesity disorder

Computational evidence

Protein change
AlphaMissense	0.0519	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -1.66	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 3.1	GERP -2.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	15.78	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 18.2% Admixed American · 10,922/59,956 alleles

Filtering AF 17.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.8%

Overall 8.84% 142,672/1,613,570 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	18.2%	5
East Asian	16.2%	6
South Asian	12.8%	8
African / African-American	10.5%	9
Remaining individualsnot grpmax-eligible	8.93%	11
Finnishnot grpmax-eligible	8.22%	12
European (non-Finnish)	7.81%	13
Middle Eastern	7.16%	14
Ashkenazi Jewishnot grpmax-eligible	4.97%	20
Amishnot grpmax-eligible	1.54%	65

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.Trp64Arg
Coding: c.190T>C
MANE Select: NM_000025
dbSNP: rs4994
Type: single nucleotide variant
Location: chr8:37966280 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41 · 2 PDB
Residue 64: a UniProt-annotated variant site (in); 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.Lys151Arg Uncertain significance ★★ ⚠ 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-trp64arg (accessed [today's date]).

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