Is ADRB2 p.Ser220Cys (c.659C>G) pathogenic?

ADRB2 p.Ser220Cys (c.659C>G) is classified Benign in ADRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0721); Low-frequency (popmax 2.58%, afr).

How common is ADRB2 p.Ser220Cys (c.659C>G) in the general population?

ADRB2 p.Ser220Cys (c.659C>G) is low-frequency (popmax 2.58%, afr) (gnomAD).

What do computational predictors say about ADRB2 p.Ser220Cys (c.659C>G)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

ADRB2 p.Ser220Cys

c.659C>G · rs3729943 · VCV703951

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.58%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -4.42	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 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 920 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	24.6	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 2.58% African / African-American · 1,934/75,028 alleles

Filtering AF 2.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.44%

Overall 0.139% 2,238/1,614,136 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.58%	39
Remaining individualsnot grpmax-eligible	0.19%	525
Admixed American	0.138%	723
Middle Eastern	0.033%	3,031
South Asian	0.0154%	6,506
European (non-Finnish)	0.0072%	13,883
Finnishnot grpmax-eligible	0.00156%	64,014

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: ADRB2
Protein: p.Ser220Cys
Coding: c.659C>G
MANE Select: NM_000024
dbSNP: rs3729943
Type: single nucleotide variant
Location: chr5:148827490 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.74 · 150 PDB
Residue 220: a UniProt-annotated variant site (in); an α-helix

Full ADRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRB2 p.Arg175= Benign ★★ same type
ADRB2 p.Gly351= Benign ★★ same type
ADRB2 p.Leu413= Benign ★★ same type
ADRB2 p.Leu84= Benign ★★ same type
ADRB2 p.Tyr366= Benign/Likely benign ★★ same type
ADRB2 p.Ala19Glu Uncertain significance ★ ⚠ same type
ADRB2 p.Arg328Trp Uncertain significance ★ ⚠ same type
ADRB2 p.Gln3Lys 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/adrb2-p-ser220cys (accessed [today's date]).

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