Is ADRB3 p.Ala42Asp (c.125C>A) pathogenic?

ADRB3 p.Ala42Asp (c.125C>A) is classified Uncertain significance in ADRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: ambiguous (0.5103); Very rare (popmax 0.00119%, nfe).

How common is ADRB3 p.Ala42Asp (c.125C>A) in the general population?

ADRB3 p.Ala42Asp (c.125C>A) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ADRB3 p.Ala42Asp (c.125C>A)?

AlphaMissense predicts ambiguous (score 0.5103) — an in-silico prediction, not a clinical call.

ADRB3 p.Ala42Asp

c.125C>A · rs2486631322 · VCV2338854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5103	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -13.23	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	23.0	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 0.00119% European (non-Finnish) · 14/1,179,500 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000959% 14/1,460,420 alleles · very rare

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.Ala42Asp
Coding: c.125C>A
MANE Select: NM_000025
dbSNP: rs2486631322
Type: single nucleotide variant
Location: chr8:37966345 (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

ADRB3 p.Ala42Val Uncertain significance ★ ⚠ same residue
ADRB3 p.Asn338Ser Uncertain significance ★★ ⚠ same type
ADRB3 p.Lys151Arg Uncertain significance ★★ ⚠ same type
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

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-ala42asp (accessed [today's date]).

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