# NM_000642.3(AGL):c.4355dup (p.Trp1453fs)

https://sugi.bio/variant/agl-p-trp1453fs

## Summary

**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.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the AGL gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to glycogen storage disease III.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (United States) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AGL is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to glycogen debranching enzyme deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Full cheeks — Very frequent (99-80%)
- Intellectual disability, mild — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Hypertriglyceridemia — Very frequent (99-80%)
- Immunodeficiency — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Myopathy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009442/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGL](https://sugi.bio/atlas/gene/AGL/) |
| Protein change (HGVS p.) | p.Trp1453fs |
| Coding change (HGVS c.) | c.4355dup |
| MANE Select transcript | [NM_000642](https://www.ncbi.nlm.nih.gov/nuccore/NM_000642) |
| Variant type | Duplication |
| Location | chr1:99916604-99916605 (GRCh38) |
| ClinVar | [VCV4814456](https://www.ncbi.nlm.nih.gov/clinvar/variation/4814456/) |

**All HGVS expressions:** `NC_000001.10:g.100382161dup`, `NC_000001.11:g.99916605dup`, `NG_012865.1:g.71522dup`, `NM_000028.3:c.4355dup`, `NM_000642.3:c.4355dup`, `NM_000643.3:c.4355dup`, `NM_000644.3:c.4355dup`, `NM_000646.3:c.4307dup`, `NM_001425325.1:c.4355dup`, `NM_001425326.1:c.4334dup`, `NM_001425327.1:c.4154dup`, `NM_001425328.1:c.4151dup`, `NM_001425329.1:c.4016dup`, `NM_001425332.1:c.3977dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.817, GERP 0.889, phastCons 0.999 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.72, pLI 1.033e-22. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 33 of 34**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,488 in the highest group · 1/1,461,034 alleles overall — very rare (popmax 8.48e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AGL** population constraint: LOEUF 0.72, pLI 1.033e-22, missense-Z 0.87709. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **glycogen storage disease III** — Definitive (AR)

## Protein context {#protein}

Residue **1453** lies in a β-strand; the 'amylo-1,6-glucosidase' region.

AlphaFold model confidence (whole protein): pLDDT 92.88, 80% of residues very-high.

**1 experimental structure(s)** (PDB): [8ZEQ](https://www.rcsb.org/structure/8ZEQ).

## What this gene does {#gene-function}

*Describes the biological roles of AGL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AGL's established molecular role includes 4-alpha-glucanotransferase activity. p.Trp1453fs falls in the amylo-1,6-glucosidase region.


### Pathways affected {#pathways}

AGL participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 4-alpha-glucanotransferase activity, amylo-alpha-1,6-glucosidase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-23.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-23 |

## Associated conditions {#conditions}

[glycogen storage disease III](https://sugi.bio/atlas/disease/glycogen-storage-disease-iii/).

**Reported phenotype names (ClinVar):** Glycogen storage disease type III, FORBES DISEASE, Cori disease.

## Similar variants {#similar}

Related AGL variant pages (same residue, condition, or type): [AGL p.Arg1270Ter](/variant/agl-p-arg1270ter), [AGL p.Arg898fs](/variant/agl-p-arg898fs), [AGL p.Asn1304fs](/variant/agl-p-asn1304fs), [AGL p.Asn84fs](/variant/agl-p-asn84fs), [AGL p.Gly1442fs](/variant/agl-p-gly1442fs), [AGL p.Ile336fs](/variant/agl-p-ile336fs), [AGL p.Ile847fs](/variant/agl-p-ile847fs), [AGL p.Leu1408fs](/variant/agl-p-leu1408fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4814456). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*