Is AAGAB p.Arg223Pro (c.668G>C) pathogenic?

AAGAB p.Arg223Pro (c.668G>C) is classified Uncertain significance in AAGAB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.0977); Ultra-rare (popmax 0.0117%, amr).

How common is AAGAB p.Arg223Pro (c.668G>C) in the general population?

AAGAB p.Arg223Pro (c.668G>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about AAGAB p.Arg223Pro (c.668G>C)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

AAGAB p.Arg223Pro

c.668G>C · VCV3258117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -5.84	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 -7.8	GERP -2.8
Regional constraint	o/e 1.20	unconstrained · MANE · 52 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	0.057	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 0.0117% Admixed American · 7/59,984 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00192% 31/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0112%	8,927
East Asian	0.00223%	44,902
African / African-American	0.00133%	74,910
European (non-Finnish)	0.00127%	78,669

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: AAGAB
Protein: p.Arg223Pro
Coding: c.668G>C
MANE Select: NM_024666
Type: single nucleotide variant
Location: chr15:67208609 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 3 PDB
Residue 223: the 'disordered' region

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

Similar variants

AAGAB p.Arg223Trp Uncertain significance ★ ⚠ same residue
AAGAB p.Arg223= Benign ★ same residue
AAGAB p.Arg124Ter Pathogenic ★★ same type
AAGAB p.Arg161Ter Pathogenic ★★ same type
AAGAB p.Gln21Ter Pathogenic ★★ same type
AAGAB p.Ala74Pro Uncertain significance ★★ ⚠ same type
AAGAB p.Arg161Gln Uncertain significance ★★ ⚠ same type
AAGAB p.Leu92Val 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/aagab-p-arg223pro (accessed [today's date]).

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