GAA p.Phe467Ser
c.1400T>C · rs2510370572 · VCV2840512
ClinGen expert panel — Lysosomal Diseases VCEP
Likely Pathogenic for glycogen storage disease II. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PP3 PM3
Curation rationale (ClinGen, verbatim)
The NM_000152.5: c.1400T>C variant in GAA is predicted to result in the missense substitution of phenylalanine by serine at amino acid 467 (p.Phe467Ser). This variant has been detected in one patient with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and on enzyme replacement therapy (Clinical Diagnostic Laboratory) (PP4_Moderate). This variant was confirmed to be in trans with c.2560C>T (p.Arg854Ter), a GAA variant classified as pathogenic by the ClinGen LD VCEP (ClinVar Variation ID: 4034, SCV001371731.1), in one patient with IOPD (Clinical Diagnostic Laboratory) (PM3). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational meta-predictor REVEL has a score of 0.941 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP on Jan 16, 2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9879 | likely pathogenic ✓ concordant with ClinVar · top 1% in GAA |
|---|---|---|
| REVEL | 0.941 | strongly pathogenic-leaning |
| SaProt | LLR -16.41 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 1.03 | unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic |
| Overall | ||
| CADD | 26.8 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- GAA
- Protein
- p.Phe467Ser
- Coding
- c.1400T>C
- MANE Select
- NM_000152
- dbSNP
- rs2510370572
- Type
- single nucleotide variant
- Location
- chr17:80110018 (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.Phe467dup Uncertain significance ★★★ same residue
- GAA p.Phe467Leu Uncertain significance ★ ⚠ same residue
- GAA p.Phe467= Likely benign ★ 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-phe467ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown