Is GAA p.Pro475= (c.1425G>A) pathogenic?

GAA p.Pro475= (c.1425G>A) is classified Conflicting classifications of pathogenicity in GAA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0183%, amr); Associated with Cardiovascular phenotype.

What condition is associated with GAA p.Pro475= (c.1425G>A)?

GAA p.Pro475= (c.1425G>A) is associated with Cardiovascular phenotype, glycogen storage disease II (ClinVar).

How common is GAA p.Pro475= (c.1425G>A) in the general population?

GAA p.Pro475= (c.1425G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

GAA p.Pro475=

c.1425G>A · rs753140491 · VCV281994

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -3.2
Overall
CADD	0.802	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,000 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00415% 67/1,612,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
African / African-American	0.00801%	12,487
European (non-Finnish)	0.00398%	25,101
South Asian	0.00329%	30,359

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.Pro475=
Coding: c.1425G>A
MANE Select: NM_000152
dbSNP: rs753140491
Type: single nucleotide variant
Location: chr17:80110043 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 475: a β-strand

Full GAA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease II

Similar variants

GAA p.Pro475Leu 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
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-pro475 (accessed [today's date]).

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