Is GAA p.Asp170= (c.510C>T) pathogenic?

GAA p.Asp170= (c.510C>T) is classified Uncertain significance in GAA (ClinVar, Expert panel, 13 submitters; last evaluated 2024-03-19). Very rare (popmax 0.00833%, amr); Associated with glycogen storage disease II.

What condition is associated with GAA p.Asp170= (c.510C>T)?

GAA p.Asp170= (c.510C>T) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Asp170= (c.510C>T) in the general population?

GAA p.Asp170= (c.510C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

GAA p.Asp170=

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.510C>T · rs564758226 · VCV280956

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

glycogen storage disease II

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.510C>T variant in GAA is a synonymous (silent) variant (p.Asp170=) that is not predicted to impact splicing (BP7, BP4). This variant has been detected in at least 14 individuals with Pompe disease (PMIDs 14695532, 30564623, 30922962, 34405923). However, in all but one individual it was found to co-occur with two additional GAA variants. Additionally, studies have shown that c.510C>T frequently occurs in cis with the c.-32-13T>G variant (pathogenic by the ClinGen Lysosomal Disease VCEP) and is associated with an earlier age of onset and lower GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (PMIDs 30922962, 34405923). RT-PCR from patients with c.510C>T and c.-32-13T>G and minigene assays demonstrate that c.510C>T modulates the aberrant splicing caused by c.-32-13T>G, but does not have a significant impact on splicing when it occurs in isolation (PMID 30922962). The highest population minor allele frequency in gnomAD v2.1.1. is 0.00008925 (11/123248 alleles) in the European (non-Finnish) population, which 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 (Variation ID: 280956). While it is uncertain if c.510C>T is causative of disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Therefore, this variant is classified as a variant of unknown significance for Pompe disease based on the 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 March 19, 2024).

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	<0.2	all four deltas below 0.2 · C>G here scores Δ0.66 · evaluated, not missing
Constraint at this position
Conservation	phyloP -12	GERP -2.7
Overall
CADD	0.855	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,028 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00478% 77/1,611,606 alleles · very rare exomes 67/1,459,266 · genomes 10/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,006
European (non-Finnish)	0.00585%	17,099
Remaining individualsnot grpmax-eligible	0.0048%	20,825

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.Asp170=
Coding: c.510C>T
MANE Select: NM_000152
dbSNP: rs564758226
Type: single nucleotide variant
Location: chr17:80105096 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 170: 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.Asp170Glu Uncertain significance ★ ⚠ same residue
GAA p.Asp170_Val171insTer Pathogenic/Likely 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
GAA c.1437+1G>A 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-asp170 (accessed [today's date]).

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