# NM_000158.4(GBE1):c.909_912del (p.Phe303fs)

https://sugi.bio/variant/gbe1-p-phe303fs

## Summary

**GBE1 p.Phe303fs (c.909_912del)** is classified **Pathogenic/Likely pathogenic** in GBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-13). No gnomAD frequency available for this variant; Associated with Glycogen storage disease IV, classic hepatic.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2107059544 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GBE1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Glycogen storage disease IV, classic hepatic.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GBE1](https://sugi.bio/atlas/gene/GBE1/) |
| Protein change (HGVS p.) | p.Phe303fs |
| Coding change (HGVS c.) | c.909_912del |
| MANE Select transcript | [NM_000158](https://www.ncbi.nlm.nih.gov/nuccore/NM_000158) |
| dbSNP | [rs2107059544](https://www.ncbi.nlm.nih.gov/snp/rs2107059544/) |
| Variant type | Deletion |
| Location | chr3:81642861-81642864 (GRCh38) |
| ClinVar | [VCV1068507](https://www.ncbi.nlm.nih.gov/clinvar/variation/1068507/) |

**All HGVS expressions:** `NC_000003.11:g.81692013_81692016del`, `NC_000003.12:g.81642862_81642865del`, `NG_011810.1:g.123937_123940del`, `NM_000158.4:c.909_912del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.675, GERP 1.72, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.211, pLI 1.475e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**GBE1** population constraint: LOEUF 1.211, pLI 1.475e-08, missense-Z -0.075477. *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 due to glycogen branching enzyme deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **303** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 96.30, 94% of residues very-high.

**3 experimental structure(s)** (PDB): [4BZY](https://www.rcsb.org/structure/4BZY), [5CLT](https://www.rcsb.org/structure/5CLT), [5CLW](https://www.rcsb.org/structure/5CLW).

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

*Describes the biological roles of GBE1 (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:** GBE1's established molecular role includes 1,4-alpha-glucan branching enzyme activity. In Reactome, GBE1 is annotated in disease pathway(s) including **Glycogen storage disease type IV (GBE1)**.

**Disease mechanism (Reactome):** GBE1 loss or alteration is curated in [Glycogen storage disease type IV (GBE1)](https://reactome.org/content/detail/R-HSA-3878781).

### Pathways affected {#pathways}

GBE1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Glycogen storage disease type IV (GBE1)](https://reactome.org/content/detail/R-HSA-3878781) | curated |
| [Glycogen synthesis](https://reactome.org/content/detail/R-HSA-3322077) | curated |

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

**Molecular function:** 1,4-alpha-glucan branching enzyme activity.

**Biological process:** glycogen biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-13.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-02 |

## Associated conditions {#conditions}

[Glycogen storage disease IV, classic hepatic](https://sugi.bio/atlas/disease/glycogen-storage-disease-iv-classic-hepatic/), [glycogen storage disease due to glycogen branching enzyme deficiency](https://sugi.bio/atlas/disease/glycogen-storage-disease-due-to-glycogen-branching-enzyme-deficiency/).

**Reported phenotype names (ClinVar):** Glycogen storage disease IV, classic hepatic, Glycogen storage disease, type IV, GSD IV, CLASSIC HEPATIC, Glycogen storage disease due to glycogen branching enzyme deficiency, AMYLOPECTINOSIS, ANDERSEN DISEASE, BRANCHER DEFICIENCY, CIRRHOSIS, FAMILIAL, WITH DEPOSITION OF ABNORMAL GLYCOGEN, GBE1 DEFICIENCY, GLYCOGEN BRANCHING ENZYME DEFICIENCY.

## Similar variants {#similar}

Related GBE1 variant pages (same residue, condition, or type): [GBE1 c.1799_1803+8del](/variant/gbe1-c-1799-1803-plus-8del), [GBE1 p.Ala16fs](/variant/gbe1-p-ala16fs), [GBE1 p.Ala9fs](/variant/gbe1-p-ala9fs), [GBE1 p.Arg156fs](/variant/gbe1-p-arg156fs), [GBE1 p.Arg468fs](/variant/gbe1-p-arg468fs), [GBE1 p.Asp169fs](/variant/gbe1-p-asp169fs), [GBE1 p.Asp24fs](/variant/gbe1-p-asp24fs), [GBE1 p.Asp413fs](/variant/gbe1-p-asp413fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1068507). 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.*