rs119103258 — PYGM

Pathogenic missense variant in muscle glycogen phosphorylase causing post-translational protein loss; homozygous or compound heterozygous carriers develop McArdle disease (glycogen storage disease type V), the second most common PYGM pathogenic allele in Spanish populations

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PYGM Trp798Arg — When a Missense Mutation Erases a Protein

Most genetic diseases work by a familiar logic: if you change a gene's sequence, you change its protein. But the PYGM Trp798Arg mutation (also written W798R or c.2392T>C) tells a stranger story. Patients who carry this variant produce normal amounts of PYGM messenger RNA — the gene is being read and copied faithfully — yet their muscle cells contain virtually no myophosphorylase11 myophosphorylase
muscle-specific glycogen phosphorylase, the enzyme encoded by PYGM that cleaves glucose-1-phosphate from glycogen at the start of exercise protein. The mutation seems to hijack a post-translational quality-control system, condemning the newly made protein to rapid degradation before it can fold and function. The result is a complete block in muscle glycogenolysis indistinguishable from a frameshift or nonsense variant.

This is McArdle disease22 McArdle disease
glycogen storage disease type V (GSD-V), an autosomal recessive metabolic myopathy first described by Brian McArdle in 1951 and caused by loss of functional myophosphorylase in skeletal muscle: exercise intolerance, painful cramps in the first minutes of exertion, and the characteristic "second wind" as blood-glucose and fatty-acid delivery eventually compensate for the absent glycogenolytic pathway.

ClinVar classifies Trp798Arg as Pathogenic33 ClinVar classifies Trp798Arg as Pathogenic
VCV000002312, criteria provided, multiple submitters, no conflicts for glycogen storage disease type V, with eleven contributing submissions.

The Mechanism

Tryptophan 798 sits in the C-terminal catalytic domain of myophosphorylase, near the region involved in dimer interface contacts and allosteric effector binding. The substitution of tryptophan (neutral, aromatic, bulky) with arginine (positively charged, flexible) creates a physicochemical mismatch that the cell's protein quality control system apparently cannot tolerate.

The critical evidence comes from an iPSC-based skeletal muscle model developed by Lucía et al.44 Lucía et al.
Lucía A et al. Creation of an iPSC-based skeletal muscle model of McArdle disease harbouring the mutation c.2392T>C (p.Trp798Arg) in the PYGM gene. Biomedicines, 2023. Patient-derived myofibers showed: (1) PYGM mRNA expression statistically indistinguishable from healthy controls; (2) complete absence of myophosphorylase protein by Western blot and immunofluorescence; and (3) PAS-positive glycogen accumulation around cell nuclei — the morphological signature of McArdle disease. The mRNA-protein discordance points to a post-translational mechanism: the mutant protein is produced but immediately recognized as misfolded and degraded, likely by the proteasomal or chaperone-mediated quality-control machinery.

This "unexpected consequence" of a missense mutation has been observed broadly across PYGM pathogenic missense variants — many of which cause complete myophosphorylase absence despite their theoretical missense status. The clinical implication is that Trp798Arg homozygotes and compound heterozygotes have the same functional deficit as patients carrying nonsense or frameshift mutations: zero functional enzyme.

The Evidence

The variant was identified as a recurrent allele in the Spanish McArdle population by Rubio et al.55 Rubio et al.
Rubio JC et al. A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients. Hum Mutat, 2007, who found it in 9 of 55 Spanish patients — making it the third most frequent PYGM mutation in Spain alongside p.R50X and p.Gly205Ser, and characterizing it as "a virtually Spanish-private mutation" not identified in British, American, German, French, or Italian cohorts.

A 2015 comprehensive update of all documented PYGM mutations by Nogales-Gadea et al.66 Nogales-Gadea et al.
Nogales-Gadea G et al. McArdle disease: update of reported mutations and polymorphisms in the PYGM gene. Hum Mutat, 2015 catalogued 147 pathogenic mutations. Trp798Arg is documented as the second most frequent pathogenic missense allele in the Spanish population, with no genotype-phenotype correlation found across PYGM variants — the specific mutation does not predict disease severity.

Vieitez et al.77 Vieitez et al.
Vieitez I et al. Molecular and clinical study of McArdle's disease in a cohort of 123 European patients. Neuromuscul Disord, 2011 confirmed the dominance of p.R50X (61.7% allelic frequency) across European populations and the population-specific distribution of secondary alleles, with no cross-population case of Trp798Arg in non-Spanish Europeans.

McArdle disease affects approximately 1 in 100,000–167,000 people globally. Life expectancy is normal; about 11% of patients develop permanent proximal weakness after age 40, and rhabdomyolysis episodes carry acute kidney injury risk.

Practical Actions

The management of McArdle disease is identical regardless of which specific PYGM pathogenic mutation is present — phenotype tracks with enzyme absence, not genotype. The most validated, genotype-specific interventions are:

Pre-exercise sucrose: 25–40 g of sucrose 5 minutes before exercise significantly improves tolerance by raising blood glucose before glycolysis demand peaks. This is the most validated nutritional intervention specific to myophosphorylase deficiency — it bypasses the glycogen block by providing circulating glucose directly.

Second-wind strategy: Starting exercise at very low intensity for 8–10 minutes allows blood-glucose delivery and fatty acid mobilization to compensate for the absent glycogenolytic pathway before effort is increased. Patients who exploit this phenomenon achieve substantially better exercise capacity.

Myoglobinuria recognition: Dark urine after exertion signals rhabdomyolysis and requires immediate rest, aggressive hydration, and emergency evaluation for acute kidney injury.

Interactions

This is an autosomal recessive variant. Compound heterozygosity — inheriting Trp798Arg on one chromosome and any other pathogenic PYGM allele (R50X, Gly205Ser, or any of the ~147 documented variants) on the other — produces full McArdle disease with zero functional myophosphorylase. The most common pairings in Spanish patients involve compound heterozygosity between Trp798Arg and p.R50X (rs116855232).

The "virtually Spanish-private" epidemiology of Trp798Arg means this allele is of greatest clinical relevance in patients of Iberian or Latin American descent. Genetic panels for McArdle disease in Spanish-ancestry individuals should explicitly include this variant alongside R50X and Gly205Ser.

Nutrient Interactions

sucrose (glucose) increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-Carrier Normal

Normal PYGM — full myophosphorylase function

You carry two copies of the reference A allele. Your myophosphorylase enzyme is produced in full, and your muscles can break down glycogen normally during exercise. You do not carry the Trp798Arg pathogenic allele and are not at risk of transmitting it to your children. The G allele is found in fewer than 1 in 10,000 people globally and is predominantly observed in Spanish and Latin American ancestry populations.

AG Carrier Carrier

Heterozygous carrier — one non-functional PYGM allele; no McArdle disease

With one functional PYGM allele, your muscle myophosphorylase activity is approximately 50% of normal — well above the threshold needed for unimpaired exercise. Obligate heterozygotes (parents of McArdle patients) show no clinical signs of the disease. The Trp798Arg allele causes protein absence through post-translational instability of the mutant protein, but this only becomes clinically significant when both copies of PYGM produce non-functional protein.

The primary significance of carrier status is reproductive. If both parents carry any pathogenic PYGM variant — regardless of which specific variant — each pregnancy has a 25% risk of producing a child with biallelic PYGM loss and McArdle disease. This probability applies when one parent carries Trp798Arg and the other carries any of the ~147 documented pathogenic PYGM alleles.

In Spanish ancestry individuals, the most likely compound heterozygous combination involves Trp798Arg paired with p.R50X — the dominant European PYGM allele with an allelic frequency of ~60% in Spanish McArdle cohorts.

GG Homozygous Homozygous

Homozygous Trp798Arg — complete myophosphorylase deficiency; McArdle disease

The Trp798Arg variant causes complete myophosphorylase deficiency through an unexpected post-translational mechanism. iPSC-derived skeletal muscle cells from a Trp798Arg patient (Lucía et al., 2023) showed PYGM mRNA levels identical to healthy controls, but zero detectable protein — with glycogen accumulating in characteristic PAS-positive clusters around cell nuclei. The mutant protein is produced but immediately recognized as misfolded and degraded.

The functional consequence is identical to loss-of-function mutations: without myophosphorylase, muscles cannot cleave glucose-1-phosphate from glycogen at the start of exercise. Glycolysis cannot be fed from internal stores; muscle cells rely entirely on blood glucose and fatty acids from the start of exertion — supplies that arrive too slowly in the first 8–10 minutes of activity, producing the characteristic cramping, weakness, and lactate-paradox signature of McArdle disease.

The "second wind" — symptomatic relief after 8–10 minutes of low-intensity exertion — reflects the point at which cardiac output, blood glucose delivery, and fatty acid mobilization sufficiently compensate for the absent glycogenolysis. Patients who learn to pace themselves through this initial period can achieve substantial aerobic fitness. Creatine kinase (CK) is persistently elevated at rest (typically 500–2,000 U/L) and rises dramatically after unguarded exertion; episodes of myoglobinuria signal rhabdomyolysis and acute kidney injury risk. Long-term prognosis is favorable with appropriate management — life expectancy is normal for most patients.