# NM_002863.5(PYGL):c.25_44dup (p.Ser15fs)

https://sugi.bio/variant/pygl-p-ser15fs

## Summary

**PYGL p.Ser15fs (c.25_44dup)** is classified **Pathogenic** in PYGL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-08). Very rare (popmax 0.00133%, afr); Associated with glycogen storage disease VI.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs786204785 · 2 submitters · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the PYGL gene that is considered disease-causing, submitted by 2 submitters, 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.Ser15fs |
| Coding change (HGVS c.) | c.25_44dup |
| MANE Select transcript | [NM_002863](https://www.ncbi.nlm.nih.gov/nuccore/NM_002863) |
| dbSNP | [rs786204785](https://www.ncbi.nlm.nih.gov/snp/rs786204785/) |
| Variant type | Duplication |
| Location | chr14:50944359-50944360 (GRCh38) |
| ClinVar | [VCV189242](https://www.ncbi.nlm.nih.gov/clinvar/variation/189242/) |

**All HGVS expressions:** `NC_000014.8:g.51411081_51411100dup`, `NC_000014.9:g.50944363_50944382dup`, `NG_012796.1:g.5152_5171dup`, `NM_001163940.2:c.25_44dup`, `NM_002863.5:c.25_44dup`

## 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 4.134, GERP 0.837, phastCons 1 — highly conserved position (PP3-type support)
- 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 1 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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: **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 **0.00133%** (afr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/74,932 in the highest group · 5/1,613,500 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,932 |
| European (non-Finnish) | 0.000339% | 294,958 |

*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 **15** lies in a β-strand; a modified residue (phosphoserine; by phk; in form phosphorylase a).

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-11-08.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2013–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-08 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2013-11-10 |

## 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, not provided, Glycogen storage disease type 6, due to phosphorylation, GSD VI, Glycogen storage disease type 6, Hepatic glycogen phosphorylase deficiency, HERS DISEASE, PHOSPHORYLASE DEFICIENCY GLYCOGEN-STORAGE DISEASE OF LIVER, none provided.

## Similar variants {#similar}

Related PYGL variant pages (same residue, condition, or type): [PYGL p.Leu305fs](/variant/pygl-p-leu305fs), [PYGL p.Arg12fs](/variant/pygl-p-arg12fs), [PYGL p.Asn408fs](/variant/pygl-p-asn408fs), [PYGL p.Leu137fs](/variant/pygl-p-leu137fs), [PYGL p.Ser639fs](/variant/pygl-p-ser639fs), [PYGL p.Ser752fs](/variant/pygl-p-ser752fs), [PYGL c.1404-1G>A](/variant/pygl-c-1404-minus-1g-a), [PYGL c.1620+1G>A](/variant/pygl-c-1620-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 189242). 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.*