Is AGL p.Trp1453fs (c.4355dup) pathogenic?

AGL p.Trp1453fs (c.4355dup) is classified Likely pathogenic in AGL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-23). Very rare (popmax 8.48e-05%, nfe); Associated with glycogen storage disease III.

What condition is associated with AGL p.Trp1453fs (c.4355dup)?

AGL p.Trp1453fs (c.4355dup) is associated with glycogen storage disease III (ClinVar).

How common is AGL p.Trp1453fs (c.4355dup) in the general population?

AGL p.Trp1453fs (c.4355dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

AGL p.Trp1453fs

Q: How is Glycogen storage disease due to glycogen debranching enzyme deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.4355dup · VCV4814456

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

glycogen storage disease III

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 33 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.82	GERP 0.89, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,488 alleles

Overall 6.84e-05% 1/1,461,034 alleles · very rare

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: AGL
Protein: p.Trp1453fs
Coding: c.4355dup
MANE Select: NM_000642
Type: Duplication
Location: chr1:99916604 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 1453: a β-strand; the 'amylo-1,6-glucosidase' region

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

Disease context

glycogen storage disease III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to glycogen debranching enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (United States)

Similar variants

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AGL p.Asn1304fs Pathogenic/Likely pathogenic ★★ same condition
AGL p.Asn84fs Pathogenic/Likely pathogenic ★★ same condition
AGL p.Gly1442fs Pathogenic ★★ same condition
AGL p.Ile336fs Pathogenic/Likely pathogenic ★★ same condition
AGL p.Ile847fs Pathogenic/Likely pathogenic ★★ same condition
AGL p.Leu1408fs Pathogenic/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/agl-p-trp1453fs (accessed [today's date]).

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