Is GAA p.Ser688Arg (c.2064C>A) pathogenic?

GAA p.Ser688Arg (c.2064C>A) is classified Uncertain significance in GAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-04). AlphaMissense: ambiguous (0.5077); Very rare (popmax 0.000681%, nfe); Associated with glycogen storage disease II.

What condition is associated with GAA p.Ser688Arg (c.2064C>A)?

GAA p.Ser688Arg (c.2064C>A) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Ser688Arg (c.2064C>A) in the general population?

GAA p.Ser688Arg (c.2064C>A) is very rare (popmax 0.000681%, nfe) (gnomAD).

What do computational predictors say about GAA p.Ser688Arg (c.2064C>A)?

AlphaMissense predicts ambiguous (score 0.5077) — an in-silico prediction, not a clinical call.

GAA p.Ser688Arg

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.2064C>A · rs140996643 · VCV2138957

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000681%, nfe)

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.5077	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -9.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP 1.3
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	19.52	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000681% European (non-Finnish) · 8/1,174,952 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000562% 9/1,600,990 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	61,996
European (non-Finnish)grpmax	0.000681%	146,869

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser688Arg
Coding: c.2064C>A
MANE Select: NM_000152
dbSNP: rs140996643
Type: single nucleotide variant
Location: chr17:80113241 (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.Ser688= Conflicting classifications of pathogenicity ★ 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-ser688arg (accessed [today's date]).

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