Is ADRB3 p.Pro326Ser (c.976C>T) pathogenic?

ADRB3 p.Pro326Ser (c.976C>T) is classified Uncertain significance in ADRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0787); Very rare (popmax 0.000349%, nfe).

How common is ADRB3 p.Pro326Ser (c.976C>T) in the general population?

ADRB3 p.Pro326Ser (c.976C>T) is very rare (popmax 0.000349%, nfe) (gnomAD).

What do computational predictors say about ADRB3 p.Pro326Ser (c.976C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

ADRB3 p.Pro326Ser

c.976C>T · VCV3839258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000349%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.22	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 1.6	GERP -5.2, phastCons 0.81
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	6.857	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 0.000349% European (non-Finnish) · 4/1,147,486 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000286% 4/1,399,886 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.Pro326Ser
Coding: c.976C>T
MANE Select: NM_000025
Type: single nucleotide variant
Location: chr8:37965494 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41 · 2 PDB
Residue 326: an α-helix

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

Similar variants

ADRB3 p.Pro326= Likely benign ★ 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-pro326ser (accessed [today's date]).

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