Is GAA p.Val442= (c.1326G>A) pathogenic?

GAA p.Val442= (c.1326G>A) is classified Uncertain significance in GAA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-12). Very rare (popmax 0.00227%, sas); Associated with glycogen storage disease II.

What condition is associated with GAA p.Val442= (c.1326G>A)?

GAA p.Val442= (c.1326G>A) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Val442= (c.1326G>A) in the general population?

GAA p.Val442= (c.1326G>A) is very rare (popmax 0.00227%, sas) (gnomAD).

GAA p.Val442=

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.1326G>A · rs773471300 · VCV2142776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00227%, sas)

Conditions

glycogen storage disease II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.44	donor gain · deltas
Pangolin	Δ0.64	loss · gain 0.12 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 0.71	GERP -0.73, phastCons 1
Overall
CADD	16.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% South Asian · 2/88,084 alleles

Filtering AF 0.000377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000141%

Overall 0.000126% 2/1,588,808 alleles · very rare exomes 2/1,436,488 · genomes 0/152,320 · 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.Val442=
Coding: c.1326G>A
MANE Select: NM_000152
dbSNP: rs773471300
Type: single nucleotide variant
Location: chr17:80108828 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 442: a β-strand

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.Val442Met 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-val442 (accessed [today's date]).

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