Is CTRB2 p.Gly223Arg (c.667G>A) pathogenic?

CTRB2 p.Gly223Arg (c.667G>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.2576); Very rare (popmax 0.00667%, afr).

How common is CTRB2 p.Gly223Arg (c.667G>A) in the general population?

CTRB2 p.Gly223Arg (c.667G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about CTRB2 p.Gly223Arg (c.667G>A)?

AlphaMissense predicts likely benign (score 0.2576) — an in-silico prediction, not a clinical call.

CTRB2 p.Gly223Arg

c.667G>A · VCV4657538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2576	likely benign
REVEL	0.597	indeterminate
SaProt	LLR -10.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.2, phastCons 0.25
Regional constraint	o/e 1.32	unconstrained · MANE · 639 bp · p 0.0022 · regional, not allelic
Overall
CADD	17.59	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 0.00667% African / African-American · 5/75,004 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00161% 26/1,614,064 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	15,001
Admixed American	0.005%	20,006
East Asian	0.00223%	44,868
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.00119%	84,286

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: CTRB2
Protein: p.Gly223Arg
Coding: c.667G>A
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75204286 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 223: a disulfide bond; the peptidase s1 domain

Full CTRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/ctrb2-p-gly223arg (accessed [today's date]).

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