GAA p.Pro205=
c.615G>A · rs141427808 · VCV196223
ClinGen expert panel — Lysosomal Diseases VCEP
Uncertain Significance for glycogen storage disease II. Applied ACMG criteria (verbatim):
PM2_Supporting BP7 BP4
Curation rationale (ClinGen, verbatim)
The NM_000152.5:c.615G>A variant in GAA is a synonymous (silent) variant (p.Pro205=) that is not predicted to impact splicing based on the computational splice predictor SpliceAI (BP4). Further, it is not in a position that is highly conserved (BP7). This variant has not been reported in a patient with Pompe disease to our knowledge. The highest population minor allele frequency in gnomAD v4.0. is 0.0004172 (38/91082 alleles) in the South Asian population. This is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (ClinVar Variation ID: 196223). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): BP4, BP7, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 7, 2026)
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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -6.2 | GERP -2.8 |
| Overall | ||
| CADD | 0.607 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0417% | 2,397 |
| Middle Eastern | 0.0166% | 6,032 |
| European (non-Finnish) | 0.00373% | 26,818 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,237 |
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.Pro205=
- Coding
- c.615G>A
- MANE Select
- NM_000152
- dbSNP
- rs141427808
- Type
- single nucleotide variant
- Location
- chr17:80105817 (GRCh38)
- Gene constraint
- LOEUF 1.008 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 92.32 · 19 PDB
Disease context
glycogen storage disease II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor 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.Pro205Ala Uncertain significance ★★ ⚠ same residue
- GAA p.Pro205Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- GAA p.Pro205Ser Uncertain significance ★ ⚠ 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-pro205 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown