Is GAA p.Ala77Ser (c.229G>T) pathogenic?

GAA p.Ala77Ser (c.229G>T) is classified Uncertain significance in GAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-15). AlphaMissense: likely benign (0.0807); Very rare (popmax 0.000509%, nfe); Associated with glycogen storage disease II.

What condition is associated with GAA p.Ala77Ser (c.229G>T)?

GAA p.Ala77Ser (c.229G>T) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Ala77Ser (c.229G>T) in the general population?

GAA p.Ala77Ser (c.229G>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about GAA p.Ala77Ser (c.229G>T)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

GAA p.Ala77Ser

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.229G>T · rs781365881 · VCV580689

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.2
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	4.589	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,814 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,612,324 alleles · very rare exomes 6/1,460,104 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00159%	62,782
European (non-Finnish)grpmax	0.000509%	196,636

Finnish 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.Ala77Ser
Coding: c.229G>T
MANE Select: NM_000152
dbSNP: rs781365881
Type: single nucleotide variant
Location: chr17:80104815 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 77: the 'disordered' region

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.Ala77= Likely benign ★★ same residue
GAA p.Ala77_Val78insAla 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

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-ala77ser (accessed [today's date]).

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