# NM_005609.4(PYGM):c.2268C>T (p.Pro756=)

https://sugi.bio/variant/pygm-p-pro756

## Summary

**PYGM p.Pro756= (c.2268C>T)** is classified **Conflicting classifications of pathogenicity** in PYGM (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0433%, nfe); Associated with glycogen storage disease V.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144229867 · 7 submitters · 1 linked condition · ultra-rare (popmax 0.0433%, nfe)

## For patients & families {#patients}

This is a change in the PYGM gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, 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.Pro756= |
| Coding change (HGVS c.) | c.2268C>T |
| MANE Select transcript | [NM_005609](https://www.ncbi.nlm.nih.gov/nuccore/NM_005609) |
| dbSNP | [rs144229867](https://www.ncbi.nlm.nih.gov/snp/rs144229867/) |
| Variant type | single nucleotide variant |
| Location | chr11:64747268-64747268 (GRCh38) |
| ClinVar | [VCV305269](https://www.ncbi.nlm.nih.gov/clinvar/variation/305269/) |

**All HGVS expressions:** `LRG_100:g.3189C>T`, `NC_000011.10:g.64747268G>A`, `NC_000011.9:g.64514740G>A`, `NG_007574.1:g.3189C>T`, `NG_013018.1:g.18448C>T`, `NM_001164716.1:c.2004C>T`, `NM_005609.4:c.2268C>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 (below), not from a missing predictor score.
- Conservation: phyloP -20, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 0.104**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0433%** (nfe) · FAF95 0.0402% · FAF99 0.0389% · 511/1,179,930 in the highest group · 549/1,614,116 alleles overall — ultra-rare (popmax 0.0433%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0433% | 2,309 |
| Remaining individuals (not grpmax-eligible) | 0.0336% | 2,977 |
| African / African-American | 0.0133% | 7,506 |
| South Asian | 0.00549% | 18,217 |
| Admixed American | 0.00333% | 30,014 |

*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 **756** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (5 Likely benign, 2 Uncertain significance).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-20 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-01 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-24 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-06-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-08-25 |

## 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, not provided, PYGM-related disorder, not specified, PYGM-related condition, MCARDLE DISEASE, MUSCLE GLYCOGEN PHOSPHORYLASE DEFICIENCY, MYOPHOSPHORYLASE DEFICIENCY, PYGM DEFICIENCY, McArdle type glycogen storage disease.

## Similar variants {#similar}

Related PYGM variant pages (same residue, condition, or type): [PYGM p.Pro756Leu](/variant/pygm-p-pro756leu), [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 305269). 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.*