# NM_002863.5(PYGL):c.715_716del (p.Val239fs)

https://sugi.bio/variant/pygl-p-val239fs

## Summary

**PYGL p.Val239fs (c.715_716del)** is classified **Likely pathogenic** in PYGL (ClinVar, Single submitter, 1 submitter). Ultra-rare (popmax 0.0165%, mid); Associated with glycogen storage disease VI.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs750699019 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

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

*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 |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PYGL is a diagnostic-grade gene on 9 Genomics England panels |

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

- Hepatomegaly — Very frequent (99-80%)
- Increased hepatic glycogen content — Very frequent (99-80%)
- Osteopenia — Frequent (79-30%)
- Osteoporosis — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Delayed puberty — Frequent (79-30%)
- Growth delay — Frequent (79-30%)
- Hypoglycemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006529/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PYGL](https://sugi.bio/atlas/gene/PYGL/) |
| Protein change (HGVS p.) | p.Val239fs |
| Coding change (HGVS c.) | c.715_716del |
| MANE Select transcript | [NM_002863](https://www.ncbi.nlm.nih.gov/nuccore/NM_002863) |
| dbSNP | [rs750699019](https://www.ncbi.nlm.nih.gov/snp/rs750699019/) |
| Variant type | Deletion |
| Location | chr14:50921012-50921013 (GRCh38) |
| ClinVar | [VCV2627506](https://www.ncbi.nlm.nih.gov/clinvar/variation/2627506/) |

**All HGVS expressions:** `NC_000014.8:g.51387731_51387732del`, `NC_000014.9:g.50921013_50921014del`, `NG_012796.1:g.28518_28519del`, `NM_001163940.2:c.613_614del`, `NM_002863.5:c.715_716del`

## 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 1.929, GERP -1.17, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.048, pLI 4.2298e-27. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 20**, 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000875% · FAF99 0.000443% · 1/6,062 in the highest group · 5/1,614,234 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| South Asian | 0.00329% | 30,362 |
| European (non-Finnish) | 8.47e-05% | 1,180,032 |

*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}

**PYGL** population constraint: LOEUF 1.048, pLI 4.2298e-27, missense-Z 0.96944. *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 VI** — Definitive (AR)

## Protein context {#protein}

Residue **239** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 92.87, 87% of residues very-high.

**19 experimental structure(s)** (PDB): [1EM6](https://www.rcsb.org/structure/1EM6), [1EXV](https://www.rcsb.org/structure/1EXV), [1FA9](https://www.rcsb.org/structure/1FA9), [1FC0](https://www.rcsb.org/structure/1FC0), [1L5Q](https://www.rcsb.org/structure/1L5Q), [1L5R](https://www.rcsb.org/structure/1L5R).

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

*Describes the biological roles of PYGL (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:** PYGL's established molecular role includes purine nucleobase binding.


### Pathways affected {#pathways}

PYGL 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:** purine nucleobase binding, ATP binding, D-glucose binding, glycogen phosphorylase activity, AMP binding, vitamin binding.

**Biological process:** glycogen metabolic process, glucose homeostasis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[glycogen storage disease VI](https://sugi.bio/atlas/disease/glycogen-storage-disease-vi/).

**Reported phenotype names (ClinVar):** Glycogen storage disease, type VI, Hepatic glycogen phosphorylase deficiency, Glycogen storage disease type 6, HERS DISEASE, PHOSPHORYLASE DEFICIENCY GLYCOGEN-STORAGE DISEASE OF LIVER, Glycogen storage disease type 6, due to phosphorylation, GSD VI.

## Similar variants {#similar}

Related PYGL variant pages (same residue, condition, or type): [PYGL c.1828-2del](/variant/pygl-c-1828-minus-2del), [PYGL c.855+14del](/variant/pygl-c-855-plus-14del), [PYGL c.*11del](/variant/pygl-c-star-11del), [PYGL p.Arg67fs](/variant/pygl-p-arg67fs), [PYGL p.Cys109fs](/variant/pygl-p-cys109fs), [PYGL p.Leu381fs](/variant/pygl-p-leu381fs), [PYGL p.Met100fs](/variant/pygl-p-met100fs), [PYGL p.Pro282fs](/variant/pygl-p-pro282fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 2627506). 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.*