Is ALPG p.Arg223Gln (c.668G>A) pathogenic?

ALPG p.Arg223Gln (c.668G>A) is classified Likely benign in ALPG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-02). AlphaMissense: ambiguous (0.4837); Ultra-rare (popmax 0.0173%, afr).

How common is ALPG p.Arg223Gln (c.668G>A) in the general population?

ALPG p.Arg223Gln (c.668G>A) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about ALPG p.Arg223Gln (c.668G>A)?

AlphaMissense predicts ambiguous (score 0.4837) — an in-silico prediction, not a clinical call.

ALPG p.Arg223Gln

c.668G>A · VCV3858319

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4837 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Computational evidence

Protein change
AlphaMissense	0.4837	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -14.56	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.63, phastCons 0.015
Regional constraint	o/e 1.03	unconstrained · MANE · 1,395 bp · p 0.6 · regional, not allelic
Overall
CADD	26.3	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 0.0173% African / African-American · 13/74,934 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00167% 27/1,613,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,764
Admixed American	0.005%	20,002
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.0011%	90,942
European (non-Finnish)	0.000593%	168,556

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: ALPG
Protein: p.Arg223Gln
Coding: c.668G>A
MANE Select: NM_031313
Type: single nucleotide variant
Location: chr2:232408286 (GRCh38)
Gene constraint: LOEUF 1.103 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.31

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

Similar variants

ALPG p.Arg498Pro Benign ★★ same type
ALPG p.Gly230= Benign ★★ same type
ALPG p.Gly500Asp Likely benign ★★ same type
ALPG p.His172= Benign/Likely benign ★★ same type
ALPG p.Leu8= Benign ★★ same type
ALPG p.Pro228Arg Benign ★★ ⚠ same type
ALPG p.Pro94Ser Benign ★★ ⚠ same type
ALPG p.Ser150= 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/alpg-p-arg223gln (accessed [today's date]).

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