Is GAA p.Pro640= (c.1920T>G) pathogenic?

GAA p.Pro640= (c.1920T>G) is classified Likely benign in GAA (ClinVar, Expert panel, 15 submitters; last evaluated 2024-05-07). Ultra-rare (popmax 0.0669%, eas); Associated with glycogen storage disease II.

What condition is associated with GAA p.Pro640= (c.1920T>G)?

GAA p.Pro640= (c.1920T>G) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Pro640= (c.1920T>G) in the general population?

GAA p.Pro640= (c.1920T>G) is ultra-rare (popmax 0.0669%, eas) (gnomAD).

GAA p.Pro640=

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.1920T>G · rs144090460 · VCV255358

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, eas)

Conditions

glycogen storage disease II

ClinGen expert panel — Lysosomal Diseases VCEP

Likely Benign for glycogen storage disease II. Applied ACMG criteria (verbatim):

BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000152.5:c.1920T>G variant in GAA is a synonymous (silent) variant that does not change the encoded amino acid (p.Pro640=) and is not predicted to impact splicing. This variant has not been reported as disease-causing in an individual with Pompe disease. It has been described as a polymorphism in a cohort of patients with infantile or juvenile-onset Pompe disease from Taiwan (PMID:18458862). It was also reported in two patients in a European cohort with limb-girdle muscle weakness without a second variant (PMID: 29149851). Thus, there is insufficient data to apply PP4. The highest population minor allele frequency in gnomAD v3.1.2 is [0.001534] (8/5184 alleles) in East Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), and lower than the threshold for BS1 (>0.005). Therefore none of the population data codes are met. This variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (-2.182) and PhastCons (0.000) (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 255358; 1-star review status) with 10 submitters classifying the variant as uncertain significance (4) or likely benign (6). In summary, this variant meets the criteria to be classified as likely benign 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. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.5
Overall
CADD	8.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0669% East Asian · 30/44,824 alleles

Filtering AF 0.0482% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.0106% 171/1,610,512 alleles · ultra-rare exomes 149/1,458,230 · genomes 22/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0669%	1,494
Finnishnot grpmax-eligible	0.0476%	2,100
Remaining individualsnot grpmax-eligible	0.0128%	7,796
European (non-Finnish)	0.00831%	12,029
South Asian	0.00554%	18,064

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.Pro640=
Coding: c.1920T>G
MANE Select: NM_000152
dbSNP: rs144090460
Type: single nucleotide variant
Location: chr17:80112907 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB

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.Pro640Leu 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
GAA c.1437+1G>A Likely pathogenic ★★★ same condition
GAA c.1437+2T>C 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-pro640 (accessed [today's date]).

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