PKLR

Chr 1ADAR

pyruvate kinase L/R

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

NCBI Gene: 5313 ENSG00000143627 UniProt: P30613 OMIM: 609712

The protein is a pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with ATP synthesis, representing the rate-limiting step of glycolysis. Mutations cause congenital nonspherocytic hemolytic anemia (pyruvate kinase deficiency), a chronic hereditary condition affecting red blood cell metabolism. Inheritance is autosomal recessive, though some forms may show autosomal dominant patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

[Adenosine triphosphate, elevated, of erythrocytes]MIM #102900

Anemia, congenital, nonspherocytic hemolytic, 2, pyruvate kinase deficientMIM #266200

UniProtPyruvate kinase hyperactivity

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · pyruvate kinase deficiency of red cells · AR · ClinGen 2024

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.92

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — PKLR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.84

OE 0.59 (0.39–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.98Z-score

OE missense 0.86 (0.78–0.94)

310 obs / 362.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.39–0.92)

0≤0.351.4

Missense OE?0.86 (0.78–0.94)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 14 / 23.7Missense obs/exp: 310 / 362.5Syn Z: -0.23

Background carrier burden — how many people carry a rare variant somewhere in PKLR?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 73

754 rare PASS variants

Rare truncating (LoF)

1 in 1,300

98 rare PASS variants

Rare synonymous (reference)

1 in 130

344 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PKLR. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 1,400
South Asian	~43k	1 in 100	1 in 2,400
Remaining (unassigned)	~30k	1 in 59	1 in 1,000
European (Finnish)	~27k	1 in 200	≈ 1 in 6,600
Admixed American	~22k	1 in 60	1 in 1,600
African / African American	~21k	1 in 71	1 in 640
East Asian	~20k	1 in 110	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — PKLR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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 Deficiency

Pyruvate Kinase Deficiency Global Longitudinal Registry

ACTIVE NOT RECRUITING

NCT03481738Agios Pharmaceuticals, Inc.Started 2018-04-23

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3