Is GAA p.Pro457Arg (c.1370C>G) pathogenic?

GAA p.Pro457Arg (c.1370C>G) is classified Pathogenic/Likely pathogenic in GAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-02). AlphaMissense: likely pathogenic (0.8558); Absent from gnomAD v4.1; Associated with glycogen storage disease II.

What condition is associated with GAA p.Pro457Arg (c.1370C>G)?

GAA p.Pro457Arg (c.1370C>G) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Pro457Arg (c.1370C>G) in the general population?

GAA p.Pro457Arg (c.1370C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GAA p.Pro457Arg (c.1370C>G)?

AlphaMissense predicts likely pathogenic (score 0.8558) — an in-silico prediction, not a clinical call.

GAA p.Pro457Arg

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.1370C>G · rs2039191855 · VCV2035414

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8558 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.8558	likely pathogenic ✓ concordant with ClinVar
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -16.69	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 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GAA
Protein: p.Pro457Arg
Coding: c.1370C>G
MANE Select: NM_000152
dbSNP: rs2039191855
Type: single nucleotide variant
Location: chr17:80109988 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 457: an α-helix; a UniProt-annotated variant site (in iopd); a UniProt-annotated variant site (in lopd)

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.Pro457Leu Pathogenic/Likely pathogenic ★★ same residue
GAA p.Pro457Ser Likely pathogenic ★ same residue
GAA p.Pro457His Conflicting classifications of pathogenicity ★ ⚠ same residue
GAA p.Pro457= Uncertain significance same residue
GAA p.Pro457Thr 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

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-pro457arg (accessed [today's date]).

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