# NM_005609.4(PYGM):c.2253C>T (p.Phe751=)

https://sugi.bio/variant/pygm-p-phe751

## Summary

**PYGM p.Phe751= (c.2253C>T)** is classified **Likely benign** in PYGM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). Very rare (popmax 0.00223%, eas); Associated with glycogen storage disease V.

**At a glance:** Likely benign · review: Single submitter · rsID rs1565531467 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the PYGM gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to glycogen storage disease V.

*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) | Adolescent, Adult, Childhood |
| Clinical trials | 15 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PYGM is a diagnostic-grade gene on 17 Genomics England panels |

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

- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Exercise intolerance — Very frequent (99-80%)
- Increased muscle glycogen content — Very frequent (99-80%)
- Glycogen accumulation in muscle fiber lysosomes — Very frequent (99-80%)
- Highly elevated creatine kinase — Very frequent (99-80%)
- Rhabdomyolysis — Frequent (79-30%)
- Recurrent myoglobinuria — Frequent (79-30%)
- Exercise-induced muscle cramps — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006528/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PYGM](https://sugi.bio/atlas/gene/PYGM/) |
| Protein change (HGVS p.) | p.Phe751= |
| Coding change (HGVS c.) | c.2253C>T |
| MANE Select transcript | [NM_005609](https://www.ncbi.nlm.nih.gov/nuccore/NM_005609) |
| dbSNP | [rs1565531467](https://www.ncbi.nlm.nih.gov/snp/rs1565531467/) |
| Variant type | single nucleotide variant |
| Location | chr11:64747283-64747283 (GRCh38) |
| ClinVar | [VCV1559724](https://www.ncbi.nlm.nih.gov/clinvar/variation/1559724/) |

**All HGVS expressions:** `LRG_100:g.3174C>T`, `NC_000011.10:g.64747283G>A`, `NC_000011.9:g.64514755G>A`, `NG_007574.1:g.3174C>T`, `NG_013018.1:g.18433C>T`, `NM_001164716.1:c.1989C>T`, `NM_005609.4:c.2253C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.405, GERP 0.812, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.15**. 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 **0.00**, acceptor gain **0.24**, donor gain **0.02**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.02**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,886 in the highest group · 1/1,614,196 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**PYGM** population constraint: LOEUF 0.962, pLI 2.8947e-22, missense-Z 1.6921. *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 V** — Definitive (AR)

## Protein context {#protein}

Residue **751** lies in a turn; a UniProt-annotated variant site (in gsd5).

AlphaFold model confidence (whole protein): pLDDT 94.41, 89% of residues very-high.

**1 experimental structure(s)** (PDB): [1Z8D](https://www.rcsb.org/structure/1Z8D).

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

*Describes the biological roles of PYGM (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:** PYGM's established molecular role includes glycogen phosphorylase activity.


### Pathways affected {#pathways}

PYGM participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** glycogen phosphorylase activity.

**Biological process:** glycogen catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-01 |

## Associated conditions {#conditions}

[glycogen storage disease V](https://sugi.bio/atlas/disease/glycogen-storage-disease-v/).

**Reported phenotype names (ClinVar):** Glycogen storage disease, type V, McArdle type glycogen storage disease, MCARDLE DISEASE, MUSCLE GLYCOGEN PHOSPHORYLASE DEFICIENCY, MYOPHOSPHORYLASE DEFICIENCY, PYGM DEFICIENCY.

## Similar variants {#similar}

Related PYGM variant pages (same residue, condition, or type): [PYGM p.Phe751del](/variant/pygm-p-phe751del), [PYGM c.1092+1G>A](/variant/pygm-c-1092-plus-1g-a), [PYGM c.1092+1G>C](/variant/pygm-c-1092-plus-1g-c), [PYGM c.1239+1G>A](/variant/pygm-c-1239-plus-1g-a), [PYGM c.1240-2A>G](/variant/pygm-c-1240-minus-2a-g), [PYGM c.1403+1G>A](/variant/pygm-c-1403-plus-1g-a), [PYGM c.1768+1G>A](/variant/pygm-c-1768-plus-1g-a), [PYGM c.1768+2T>G](/variant/pygm-c-1768-plus-2t-g).

### 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 1559724). 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.*