Is ADRB3 p.Ala375Pro (c.1123G>C) pathogenic?

ADRB3 p.Ala375Pro (c.1123G>C) is classified Uncertain significance in ADRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely benign (0.0625); Very rare (popmax 0.00276%, afr).

How common is ADRB3 p.Ala375Pro (c.1123G>C) in the general population?

ADRB3 p.Ala375Pro (c.1123G>C) is very rare (popmax 0.00276%, afr) (gnomAD).

What do computational predictors say about ADRB3 p.Ala375Pro (c.1123G>C)?

AlphaMissense predicts likely benign (score 0.0625) — an in-silico prediction, not a clinical call.

ADRB3 p.Ala375Pro

c.1123G>C · VCV3502695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00276%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0625	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.41	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 -0.065	GERP -2.1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	14.55	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 0.00276% African / African-American · 2/72,356 alleles

Filtering AF 0.000459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000172%

Overall 0.000259% 4/1,542,570 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00276%	36,178
Finnishnot grpmax-eligible	0.00171%	58,378
European (non-Finnish)	8.74e-05%	1,144,750

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.Ala375Pro
Coding: c.1123G>C
MANE Select: NM_000025
Type: single nucleotide variant
Location: chr8:37965347 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41 · 2 PDB

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

Similar variants

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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.Trp64Arg Benign ★★ same type
ADRB3 p.Ala130Thr 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-ala375pro (accessed [today's date]).

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