PKLR

Chr 1

pyruvate kinase L/R

Also known as: CNSHA2, PK1, PKL, PKRL, RPK

NCBI Gene: 5313ENSG00000143627UniProt: P30613

The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtPyruvate kinase hyperactivity
UniProtAnemia, congenital, non-spherocytic hemolytic, 2
474
ClinVar variants
132
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— PKLR
🧬
Gene-Disease Validity (ClinGen)
pyruvate kinase deficiency of red cells · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
132 Pathogenic / Likely Pathogenic· 244 VUS of 474 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.92LOEUF
pLI 0.000
Z-score 1.84
OE 0.59 (0.39–0.92)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.98Z-score
OE missense 0.86 (0.78–0.94)
310 obs / 362.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.59 (0.39–0.92)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.78–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 14 / 23.7Missense obs/exp: 310 / 362.5Syn Z: -0.23

ClinVar Variant Classifications

474 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic71
VUS244
Likely Benign44
Benign9
Conflicting45
61
Pathogenic
71
Likely Pathogenic
244
VUS
44
Likely Benign
9
Benign
45
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
23
10
28
0
61
Likely Pathogenic
13
46
11
1
71
VUS
1
189
49
5
244
Likely Benign
0
0
21
23
44
Benign
0
0
8
1
9
Conflicting
—45
Total3724511730474

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PKLR · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — PKLR
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic control of erythropoiesis.
Tumburu L et al.·Curr Opin Hematol
2017Review
Molecular heterogeneity of pyruvate kinase deficiency.
Bianchi P et al.·Haematologica
2020Review
Updates and advances in pyruvate kinase deficiency.
Luke N et al.·Trends Mol Med
2023Review
USP7 promotes the malignant progression of osteosarcoma through the KPNA2/PKLR axis.
Wang M et al.·Cell Signal
2025
Pyruvate kinase deficiency in children.
Chonat S et al.·Pediatr Blood Cancer
2021
Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.
Chen WY et al.·Redox Biol
2023
The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis.
Jia Y et al.·Arthritis Res Ther
2025
Targeted next-generation sequencing identifies eighteen novel mutations expanding the molecular and clinical spectrum of PKLR gene disorders in the Indian population.
Dongerdiye R et al.·Ann Hematol
2023
Clinical outcome and genotype analysis of four Chinese children with pyruvate kinase deficiency.
Xie F et al.·Mol Genet Genomic Med
2023
Genetic variants of PKLR are associated with acute pain in sickle cell disease.
Wang X et al.·Blood Adv
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Pyruvate Kinase Deficiency

Pyruvate Kinase Deficiency Global Longitudinal Registry

ACTIVE NOT RECRUITING
NCT03481738Agios Pharmaceuticals, Inc.Started 2018-04-23
Pyruvate Kinase Deficiency

Clinical Trial to Evaluate the Efficacy of Gene Therapy for Pyruvate Kinase Deficiency

NOT YET RECRUITING
NCT06422351Phase PHASE2Rocket Pharmaceuticals Inc.Started 2024-08
RP-L301
Sickle CellPKLR VariantsAdenosine Triphosphate Activities

Genotype -Phenotype Correlation of PKLR Variants With Pyruvate Kinase, 2,3-Diphosphglycerate and Adenosine Triphosphate Activities in Red Blood Cells of People With Sickle Cell Disease

RECRUITING
NCT03685721National Heart, Lung, and Blood Institute (NHLBI)Started 2018-10-11
Pyruvate Kinase DeficiencyPyruvate Kinase Deficiency AnemiaHereditary Hemolytic Anemia

Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms

ACTIVE NOT RECRUITING
NCT04902833Massachusetts General HospitalStarted 2022-02-01
Blood Draw

External Resources

Links to major genomics databases and tools