Is GAA p.Arg527= (c.1581G>A) pathogenic?

GAA p.Arg527= (c.1581G>A) is classified Benign in GAA (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Common (popmax 28.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with glycogen storage disease II.

What condition is associated with GAA p.Arg527= (c.1581G>A)?

GAA p.Arg527= (c.1581G>A) is associated with glycogen storage disease II (ClinVar).

GAA p.Arg527=

Q: How common is GAA p.Arg527= (c.1581G>A) in the general population?

GAA p.Arg527= (c.1581G>A) is common (popmax 28.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Glycogen storage disease due to acid maltase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1581G>A · rs1042396 · VCV92466

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 28.1%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

glycogen storage disease II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -1.9, phastCons 1
Overall
CADD	6.991	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.1% European (non-Finnish) · 331,786/1,179,854 alleles

Filtering AF 28% ClinGen BA1/BS1 input FAF95, joint · FAF99 28%

Overall 25.7% 415,305/1,613,658 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	28.1%	4
Middle Eastern	25.8%	4
Ashkenazi Jewishnot grpmax-eligible	25.4%	4
Remaining individualsnot grpmax-eligible	24.9%	4
Finnishnot grpmax-eligible	23.4%	4
Admixed American	23.3%	4
South Asian	21.7%	5
Amishnot grpmax-eligible	21.4%	5
East Asian	12%	8
African / African-American	6.21%	16

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: GAA
Protein: p.Arg527=
Coding: c.1581G>A
MANE Select: NM_000152
dbSNP: rs1042396
Type: single nucleotide variant
Location: chr17:80110970 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 527: a β-strand

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

Disease context

glycogen storage disease II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to acid maltase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GAA p.Arg527Gly Uncertain significance ★ ⚠ same residue
GAA p.Arg527Lys Uncertain significance ★ ⚠ same residue
GAA p.Arg527fs Pathogenic ★★★ same residue
GAA c.1076-1G>C Pathogenic ★★★ same condition
GAA c.1076-22T>G Pathogenic ★★★ same condition
GAA c.1194+5G>A Likely pathogenic ★★★ same condition
GAA c.1326+1G>A Pathogenic ★★★ same condition
GAA c.1327-2A>G Pathogenic ★★★ same condition

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/gaa-p-arg527 (accessed [today's date]).

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