# NM_000158.4(GBE1):c.141C>T (p.Arg47=)

https://sugi.bio/variant/gbe1-p-arg47

## Summary

**GBE1 p.Arg47= (c.141C>T)** is classified **Likely pathogenic** in GBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Very rare (popmax 0.0011%, sas); Associated with glycogen storage disease due to glycogen branching enzyme deficiency.

**At a glance:** Likely pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 0.0011%, sas)

## 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 due to glycogen branching enzyme deficiency.

*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) | All ages |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GBE1 is a diagnostic-grade gene on 23 Genomics England panels |

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

- Decreased liver function — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Generalized abnormality of skin — Very frequent (99-80%)
- Abnormal muscle glycogen content — Very frequent (99-80%)
- Abnormal cardiomyocyte morphology — Very frequent (99-80%)
- Abnormal neuron branching — Very frequent (99-80%)
- Motor delay — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002520/index) · [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.Arg47= |
| Coding change (HGVS c.) | c.141C>T |
| MANE Select transcript | [NM_000158](https://www.ncbi.nlm.nih.gov/nuccore/NM_000158) |
| Variant type | single nucleotide variant |
| Location | chr3:81761377-81761377 (GRCh38) |
| ClinVar | [VCV4789826](https://www.ncbi.nlm.nih.gov/clinvar/variation/4789826/) |

**All HGVS expressions:** `NC_000003.11:g.81810528G>A`, `NC_000003.12:g.81761377G>A`, `NG_011810.1:g.5424C>T`, `NG_011810.2:g.5268C>T`, `NG_100042.2:g.44G>A`, `NM_000158.3:c.141C>T`, `NM_000158.4:c.141C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.98) — consistent with the pathogenic call
- Conservation: phyloP 5.72, GERP 1.37, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 29.2**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.98**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.98**.
- Pangolin: Δ**0.81** (gain), gain 0.81 / loss 0.61. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000544% · FAF99 0.00043% · 1/90,976 in the highest group · 13/1,454,934 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 90,976 |
| European (non-Finnish) | 0.00102% | 97,948 |

*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 **47** lies in an α-helix.

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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-08 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-30 |

## Associated conditions {#conditions}

[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, type IV, Glycogen storage disease IV, classic hepatic, AMYLOPECTINOSIS, ANDERSEN DISEASE, BRANCHER DEFICIENCY, CIRRHOSIS, FAMILIAL, WITH DEPOSITION OF ABNORMAL GLYCOGEN, GBE1 DEFICIENCY, GLYCOGEN BRANCHING ENZYME DEFICIENCY, GLYCOGENOSIS IV, GSD IV.

## Similar variants {#similar}

Related GBE1 variant pages (same residue, condition, or type): [GBE1 c.1109-1G>T](/variant/gbe1-c-1109-minus-1g-t), [GBE1 c.1236+1G>A](/variant/gbe1-c-1236-plus-1g-a), [GBE1 c.1336-1G>A](/variant/gbe1-c-1336-minus-1g-a), [GBE1 c.143+1G>A](/variant/gbe1-c-143-plus-1g-a), [GBE1 c.143+2T>C](/variant/gbe1-c-143-plus-2t-c), [GBE1 c.144-1G>C](/variant/gbe1-c-144-minus-1g-c), [GBE1 c.1618+1G>A](/variant/gbe1-c-1618-plus-1g-a), [GBE1 c.1803+2T>C](/variant/gbe1-c-1803-plus-2t-c).

### 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 4789826). 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.*