Is GAA p.Pro75Ser (c.223C>T) pathogenic?

GAA p.Pro75Ser (c.223C>T) is classified Uncertain significance in GAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-04). AlphaMissense: likely benign (0.0696); Ultra-rare (popmax 0.0154%, sas); Associated with glycogen storage disease II.

What condition is associated with GAA p.Pro75Ser (c.223C>T)?

GAA p.Pro75Ser (c.223C>T) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Pro75Ser (c.223C>T) in the general population?

GAA p.Pro75Ser (c.223C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about GAA p.Pro75Ser (c.223C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

GAA p.Pro75Ser

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.223C>T · rs755561471 · VCV567275

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.24	GERP -0.073
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	6.129	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 0.0154% South Asian · 14/90,994 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00093% 15/1,612,262 alleles · ultra-rare exomes 13/1,460,052 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,500
Remaining individualsnot grpmax-eligible	0.0016%	62,440

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.Pro75Ser
Coding: c.223C>T
MANE Select: NM_000152
dbSNP: rs755561471
Type: single nucleotide variant
Location: chr17:80104809 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 75: 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.Pro75Arg Uncertain significance ⚠ same residue
GAA p.Pro75= 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
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-pro75ser (accessed [today's date]).

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