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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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PKLR
pyruvate kinase L/R
Chromosome 1 Β· 1q22
NCBI Gene: 5313Ensembl: ENSG00000143627.19HGNC: HGNC:9020UniProt: P30613
143PubMed Papers
2Diseases
0Drugs
113Pathogenic Variants
FUNCTIONAL ROLE
Hub GeneKinase
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
pyruvate kinase activityprotein bindingextracellular exosomecellular response to insulin stimulusPyruvate kinase hyperactivityAnemia, congenital, non-spherocytic hemolytic, 2
✦AI Summary

PKLR encodes pyruvate kinase L/R, a critical glycolytic enzyme catalyzing phosphoenolpyruvate conversion to pyruvate with ATP synthesis 1. This enzyme plays essential roles in both erythrocyte energy metabolism and hepatic glucose metabolism 2. Primary deficiency of PKLR causes congenital non-spherocytic hemolytic anemia due to impaired red blood cell glycolysis and energy depletion 13. Even never-transfused PK deficiency patients exhibit elevated comorbidities including osteoporosis, liver cirrhosis, and pulmonary hypertension 1. Regularly transfused patients face additional complications including iron overload and thrombosis 1. Beyond hemolysis, PKLR functions as a metabolic regulator in liver disease pathogenesis. PKLR is implicated in metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma progression 2. In pancreatic cancer, HNF-1Ξ± transcriptionally upregulates PKLR to promote proliferation and apoptosis resistance 4. Genetically, PKLR variants exhibit pathogen-selection signatures. Certain haplotypes associated with malaria resistance paradoxically increase susceptibility to intracellular pathogens including Mycobacterium leprae and tuberculosis 5. Environmental stressors like dioxin exposure downregulate PKLR enzyme activity despite increased gene expression, affecting individuals in contaminated regions 6.

Sources cited
1
PKLR mutations cause hemolytic anemia through defective RBC glycolysis; PK deficiency patients have higher rates of osteoporosis, liver cirrhosis, pulmonary hypertension, and iron overload
PMID: 33370479
2
PKLR is a key regulator of hepatic glucose metabolism and identified as pivotal gene in MASLD and HCC progression
PMID: 40221236
3
PKLR gene deficiency is a rare erythroid metabolic disease causing energetic imbalance and hemolysis in erythrocytes; gene editing approaches show feasibility for therapeutic correction
PMID: 31618280
4
Dioxin exposure increases PKLR gene copy number and expression but decreases pyruvate kinase enzyme activity; SNP rs3020781 associated with dioxin exposure
PMID: 37060958
5
HNF-1Ξ± transcriptionally upregulates PKLR in pancreatic cancer to promote cell proliferation and apoptosis resistance via two binding sites in PKLR promoter
PMID: 32072180
6
PKLR SNP haplotypes exhibit pathogen selection signatures; variants selected for malaria resistance are associated with increased susceptibility to mycobacterial infections including leprosy and tuberculosis
PMID: 34449765
7
PKLR identified as rare genetic variant affecting erythropoiesis through GWAS and sequencing studies
PMID: 28212192
Disease Associationsβ“˜2
Anemia, congenital, non-spherocytic hemolytic, 2UniProt
Pyruvate kinase hyperactivityUniProt
Pathogenic Variants113
NM_000298.6(PKLR):c.1595G>C (p.Arg532Pro)Likely pathogenic
not provided|Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2026β†’ Residue 532
NM_000298.6(PKLR):c.993C>A (p.Asp331Glu)Pathogenic
not provided|Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2026β†’ Residue 331
NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)Pathogenic
Pyruvate kinase deficiency of red cells|Pyruvate kinase hyperactivity|not provided|Pyruvate kinase hyperactivity;Pyruvate kinase deficiency of red cells|See cases|PKLR-related disorder
β˜…β˜…β˜†β˜†2026β†’ Residue 486
NM_000298.6(PKLR):c.307del (p.Arg103fs)Pathogenic
not provided|Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2026β†’ Residue 103
NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)Pathogenic
Pyruvate kinase deficiency of red cells|not provided|PKLR-related disorder|Congenital anemia
β˜…β˜…β˜†β˜†2026β†’ Residue 510
NM_000298.6(PKLR):c.1179T>A (p.Asn393Lys)Likely pathogenic
not provided
β˜…β˜…β˜†β˜†2026β†’ Residue 393
NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)Pathogenic
Pyruvate kinase deficiency of red cells|not provided|Pyruvate kinase deficiency of red cells;Pyruvate kinase hyperactivity
β˜…β˜…β˜†β˜†2025β†’ Residue 241
NM_000298.6(PKLR):c.1528C>T (p.Arg510Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 510
NM_000298.6(PKLR):c.1436G>A (p.Arg479His)Pathogenic
Pyruvate kinase deficiency of red cells|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 479
NM_000298.6(PKLR):c.823G>A (p.Gly275Arg)Likely pathogenic
not provided|Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2025β†’ Residue 275
NM_000298.6(PKLR):c.1269G>A (p.Ala423=)Pathogenic
Pyruvate kinase deficiency of red cells|not provided|Pyruvate kinase hyperactivity;Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2025β†’ Residue 423
NM_000298.6(PKLR):c.1462C>T (p.Arg488Ter)Pathogenic
not provided|Pyruvate kinase deficiency of red cells
β˜…β˜…β˜†β˜†2025β†’ Residue 488
NM_000298.6(PKLR):c.994_1003dup (p.Val335fs)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 335
NM_000298.6(PKLR):c.628_629del (p.Val210fs)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 210
NM_000298.6(PKLR):c.1151C>T (p.Thr384Met)Pathogenic
Pyruvate kinase deficiency of red cells|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 384
NM_000298.6(PKLR):c.1501C>T (p.Gln501Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 501
NM_000298.6(PKLR):c.1178A>G (p.Asn393Ser)Pathogenic
not provided|Pyruvate kinase deficiency of red cells|Pyruvate kinase hyperactivity
β˜…β˜…β˜†β˜†2025β†’ Residue 393
NM_000298.6(PKLR):c.880G>A (p.Val294Met)Likely pathogenic
Pyruvate kinase deficiency of red cells|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 294
NM_000298.6(PKLR):c.1091G>A (p.Gly364Asp)Pathogenic
not provided|PKLR-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 364
NM_000298.6(PKLR):c.625_637del (p.Arg209fs)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 209
View on ClinVar β†—
Related Genes
TALDO1Protein interaction100%ME1Protein interaction99%ME2Protein interaction99%NME1-NME2Protein interaction96%ME3Protein interaction96%ENO1Protein interaction96%
Tissue Expression

No tissue expression data available for this gene.

Gene Interaction Network
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PKLRTALDO1ME1ME2NME1-NME2ME3ENO1
PROTEIN STRUCTURE
Preparing viewer…
PDB7FS3 Β· 1.66 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.90LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.69 [0.53–0.90]
RankingsWhere PKLR stands among ~20K protein-coding genes
  • #3,204of 20,598
    Most Researched143 Β· top quartile
  • #689of 5,498
    Most Pathogenic Variants113 Β· top quartile
  • #8,140of 17,882
    Most Constrained (LOEUF)0.90
Genes detectedPKLR
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Comorbidities and complications in adults with pyruvate kinase deficiency.
PMID: 33370479
Eur J Haematol Β· 2021
1.00
2
Targeting PKLR in liver diseases.
PMID: 40221236
Trends Endocrinol Metab Β· 2025
0.90
3
Gene editing of PKLR gene in human hematopoietic progenitors through 5' and 3' UTR modified TALEN mRNA.
PMID: 31618280
PLoS One Β· 2019
0.80
4
Association of PKLR gene copy number, expression levels and enzyme activity with 2,3,7,8-TCDD exposure in individuals exposed to Agent Orange/Dioxin in Vietnam.
PMID: 37060958
Chemosphere Β· 2023
0.70
5
Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice.
PMID: 35277933
J Cachexia Sarcopenia Muscle Β· 2022
0.60