GAA p.Phe241fs
c.722_723del · rs2039116471 · VCV932903
ClinGen expert panel — Lysosomal Diseases VCEP
Pathogenic for glycogen storage disease II. Applied ACMG criteria (verbatim):
PM2 PVS1 PM3_Strong PP4
Curation rationale (ClinGen, verbatim)
This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. This data meets PM3_Strong. Additional cases have been reported, but did not meet PP4 (PMID 28838325). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 4 of 20 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 3.2 | GERP 1.4, phastCons 1 |
| Overall | ||
| CADD | 33.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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.Phe241fs
- Coding
- c.722_723del
- MANE Select
- NM_000152
- dbSNP
- rs2039116471
- Type
- Deletion
- Location
- chr17:80107585 (GRCh38)
- Gene constraint
- LOEUF 1.008 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 92.32 · 19 PDB
- Residue 241
- a β-strand
Disease context
glycogen storage disease II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: disorder of glycogen metabolism
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.Phe241Leu Uncertain significance ★★ ⚠ same residue
- GAA p.Phe241= Likely benign ★ same residue
- GAA c.1551+3_1551+6del Pathogenic ★★★ same condition
- GAA c.2189+459_*546del Pathogenic ★★★ same condition
- GAA c.2481+110_2646+39del Pathogenic ★★★ same condition
- GAA p.Ala14fs Pathogenic ★★★ same condition
- GAA p.Ala382fs Pathogenic ★★★ same condition
- GAA p.Arg154_Thr155del Likely 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-phe241fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown