Is ADRB3 p.Pro279Ser (c.835C>T) pathogenic?

ADRB3 p.Pro279Ser (c.835C>T) is classified Uncertain significance in ADRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.1193); Ultra-rare (popmax 0.0128%, afr).

How common is ADRB3 p.Pro279Ser (c.835C>T) in the general population?

ADRB3 p.Pro279Ser (c.835C>T) is ultra-rare (popmax 0.0128%, afr) (gnomAD).

What do computational predictors say about ADRB3 p.Pro279Ser (c.835C>T)?

AlphaMissense predicts likely benign (score 0.1193) — an in-silico prediction, not a clinical call.

ADRB3 p.Pro279Ser

c.835C>T · VCV4638656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1193 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1193	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.80	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	GERP 0.47, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,248 bp · p 0.4 · regional, not allelic
Overall
CADD	19.15	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 0.0128% African / African-American · 9/70,528 alleles

Filtering AF 0.00659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00493%

Overall 0.000783% 12/1,532,224 alleles · ultra-rare exomes 6/1,380,092 · genomes 6/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0128%	7,836
East Asian	0.00256%	39,034
Remaining individualsnot grpmax-eligible	0.00169%	59,224
European (non-Finnish)	8.77e-05%	1,140,130

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.Pro279Ser
Coding: c.835C>T
MANE Select: NM_000025
Type: single nucleotide variant
Location: chr8:37965635 (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.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
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-pro279ser (accessed [today's date]).

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