Is GAA p.Arg375Ser (c.1123C>A) pathogenic?

GAA p.Arg375Ser (c.1123C>A) is classified Likely pathogenic in GAA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-25). AlphaMissense: likely pathogenic (0.8938); Very rare (popmax 0.00133%, afr); Associated with glycogen storage disease II.

What condition is associated with GAA p.Arg375Ser (c.1123C>A)?

GAA p.Arg375Ser (c.1123C>A) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Arg375Ser (c.1123C>A) in the general population?

GAA p.Arg375Ser (c.1123C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about GAA p.Arg375Ser (c.1123C>A)?

AlphaMissense predicts likely pathogenic (score 0.8938) — an in-silico prediction, not a clinical call.

GAA p.Arg375Ser

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.1123C>A · rs372486238 · VCV2698939

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.8938	likely pathogenic ✓ concordant with ClinVar · top 10% in GAA
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -15.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	31.0	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 0.00133% African / African-American · 1/75,030 alleles

Overall 6.2e-05% 1/1,612,974 alleles · very rare exomes 1/1,460,664 · genomes 0/152,310 · joint denominator

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.Arg375Ser
Coding: c.1123C>A
MANE Select: NM_000152
dbSNP: rs372486238
Type: single nucleotide variant
Location: chr17:80108536 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 375: a UniProt-annotated variant site (in iopd; extremely low residual enzymatic activity)

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.Arg375Leu Pathogenic ★★★ same residue
GAA p.Arg375Cys Uncertain significance ★★★ ⚠ same residue
GAA p.Arg375His 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

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-arg375ser (accessed [today's date]).

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