PKLR

Chr 1ADAR

pyruvate kinase L/R

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

NCBI Gene: 5313ENSG00000143627UniProt: P30613OMIM: 609712

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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismAD/ARLOEUF 0.922 OMIM phenotypes
Clinical Summary— PKLR
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Gene-Disease Validity (ClinGen)
pyruvate kinase deficiency of red cells · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
119 unique Pathogenic / Likely Pathogenic· 240 VUS of 464 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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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

This gene — mechanism propensity

DN
0.79top 25%
GOF
0.6639th %ile
LOF
0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

464 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic70
VUS240
Likely Benign45
Benign9
Conflicting48
49
Pathogenic
70
Likely Pathogenic
240
VUS
45
Likely Benign
9
Benign
48
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
10
5
1
49
Likely Pathogenic
20
47
2
1
70
VUS
2
191
42
5
240
Likely Benign
0
0
21
24
45
Benign
0
0
8
1
9
Conflicting
—48
Total552487832461

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap PKLR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

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