Glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Summary

Glycogen storage disease due to phosphoglycerate kinase 1 deficiency (MONDO:0010392) is a disease caused by PGK1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PGK1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 117
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001878	Hemolytic anemia	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002904	Hyperbilirubinemia	Frequent (30-79%)
HP:0002913	Myoglobinuria	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003201	Rhabdomyolysis	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0009020	Exercise-induced muscle fatigue	Frequent (30-79%)
HP:0012638	Abnormality of nervous system physiology	Frequent (30-79%)
HP:0020062	Decreased hemoglobin concentration	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000556	Retinal dystrophy	Very rare (<1-4%)
HP:0000618	Blindness	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to phosphoglycerate kinase 1 deficiency
Mondo ID	MONDO:0010392
MeSH	C567067
OMIM	300653
Orphanet	713
DOID	DOID:0111933
ICD-11	1396572570
NCIT	C126738
UMLS	C1970848
MedGen	410166
GARD	0007389
NORD	1577
Is cancer (heuristic)	no

Also known as: glycogen storage disease caused by mutation in PGK1 · glycogen storage disease due to phosphoglycerate kinase 1 deficiency · glycogenosis due to phosphoglycerate kinase 1 deficiency · GSD due to phosphoglycerate kinase 1 deficiency · PGK deficiency · PGK1 glycogen storage disease · phosphoglycerate kinase 1 deficiency, X-linked recessive · Phosphoglycerate Kinase Deficiency · Phosphoglycerate kinase deficiency

Data availability: 117 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

117 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 18 conflicting classifications of pathogenicity, 16 pathogenic, 12 benign/likely benign, 3 likely benign, 2 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3764516	PGK1, IVS4, G-T, 417+1	PGK1	Pathogenic	no assertion criteria provided
3764517	G213G	PGK1	Pathogenic	no assertion criteria provided
3764518	G372S	PGK1	Pathogenic	no assertion criteria provided
3764519	A353P	PGK1	Pathogenic	no assertion criteria provided
3764520	G317D	PGK1	Pathogenic	no assertion criteria provided
9942	NM_000291.4(PGK1):c.802G>A (p.Asp268Asn)	PGK1	Pathogenic	no assertion criteria provided
9943	NM_000291.4(PGK1):c.617G>C (p.Arg206Pro)	PGK1	Pathogenic	no assertion criteria provided
9944	NM_000291.4(PGK1):c.796_798delinsATG (p.Val266Met)	PGK1	Pathogenic	no assertion criteria provided
9946	NM_000291.4(PGK1):c.263T>C (p.Leu88Pro)	PGK1	Pathogenic	no assertion criteria provided
9947	NM_000291.4(PGK1):c.473G>T (p.Gly158Val)	PGK1	Pathogenic	no assertion criteria provided
9948	NM_000291.4(PGK1):c.946T>C (p.Cys316Arg)	PGK1	Pathogenic	no assertion criteria provided
9951	NM_000291.4(PGK1):c.854A>T (p.Asp285Val)	PGK1	Pathogenic	no assertion criteria provided
9952	NM_000291.4(PGK1):c.140T>A (p.Ile47Asn)	PGK1	Pathogenic	no assertion criteria provided
9953	NM_000291.4(PGK1):c.959G>A (p.Ser320Asn)	PGK1	Pathogenic	no assertion criteria provided
9954	NM_000291.4(PGK1):c.491A>T (p.Asp164Val)	PGK1	Pathogenic	criteria provided, multiple submitters, no conflicts
9956	NM_000291.4(PGK1):c.1132A>C (p.Thr378Pro)	PGK1	Pathogenic	no assertion criteria provided
1687119	NM_000291.4(PGK1):c.150C>G (p.Cys50Trp)	PGK1	Likely pathogenic	no assertion criteria provided
9955	NM_000291.4(PGK1):c.756+5G>A	PGK1	Likely pathogenic	criteria provided, single submitter
1163197	NM_000291.4(PGK1):c.1192G>A (p.Ala398Thr)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1488170	NM_000291.4(PGK1):c.929G>A (p.Gly310Asp)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1654832	NM_000291.4(PGK1):c.552G>C (p.Lys184Asn)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167466	NM_000291.4(PGK1):c.639C>T (p.Gly213=)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167467	NM_000291.4(PGK1):c.1114G>A (p.Gly372Ser)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1693792	NM_000291.4(PGK1):c.761G>C (p.Gly254Ala)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805130	NM_000291.4(PGK1):c.522C>T (p.Ser174=)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2047687	NM_000291.4(PGK1):c.40G>C (p.Val14Leu)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2081984	NM_000291.4(PGK1):c.146T>A (p.Phe49Tyr)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2573046	NM_000291.4(PGK1):c.545C>T (p.Pro182Leu)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598446	NM_000291.4(PGK1):c.409G>T (p.Gly137Trp)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598450	NM_000291.4(PGK1):c.506C>T (p.Ala169Val)	PGK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PGK1	Definitive	X-linked	glycogen storage disease due to phosphoglycerate kinase 1 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGK1	Orphanet:713	Glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGK1	HGNC:8896	ENSG00000102144	P00558	Phosphoglycerate kinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGK1	Phosphoglycerate kinase 1	Catalyzes one of the two ATP producing reactions in the glycolytic pathway via the reversible conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGK1	Kinase	yes		Phosphoglycerate_kinase, Phosphoglycerate_kinase_N, Phosphoglycerate_kinase_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus squamous epithelium	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGK1	295	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PGK1	7,483

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PGK1	P00558	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Manipulation of host energy metabolism	1	5710.0×	7e-04	PGK1
Gluconeogenesis	1	439.2×	0.004	PGK1
Glycolysis	1	285.5×	0.004	PGK1
MTOR signalling	1	265.6×	0.004	PGK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of pyruvate decarboxylation to acetyl-CoA	1	8426.0×	9e-04	PGK1
plasminogen activation	1	1296.3×	0.003	PGK1
canonical glycolysis	1	702.2×	0.004	PGK1
glycolytic process	1	383.0×	0.005	PGK1
gluconeogenesis	1	324.1×	0.005	PGK1
epithelial cell differentiation	1	175.5×	0.007	PGK1
negative regulation of angiogenesis	1	168.5×	0.007	PGK1
cellular response to hypoxia	1	121.2×	0.008	PGK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PGK1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PGK1	22	Binding:22

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PGK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PGK1	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00592540	Not specified	COMPLETED	Unrelated Donor BMT for Treatment of Patients With PGK Deficiency
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy