Pyruvate kinase hyperactivity

Summary

Pyruvate kinase hyperactivity (MONDO:0007067) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate kinase hyperactivity
Mondo ID	MONDO:0007067
EFO	EFO:0005840
MeSH	C566310
OMIM	102900
UMLS	C1863224
MedGen	350114
GARD	0024521
Is cancer (heuristic)	no

Also known as: pyruvate kinase hyperactivity

Data availability: 14 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › pyruvate metabolism disorder › pyruvate kinase hyperactivity

Related subtypes (3): mitochondrial pyruvate carrier deficiency, disorder of glycolysis, pyruvate dehydrogenase deficiency

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

14 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 1 affects, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1187215	NM_000298.6(PKLR):c.1178A>G (p.Asn393Ser)	PKLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1513	NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)	PKLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1517	NM_000298.6(PKLR):c.1269G>A (p.Ala423=)	PKLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280113	NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)	PKLR	Pathogenic	criteria provided, multiple submitters, no conflicts
292815	NM_000298.6(PKLR):c.391_393del (p.Ile131del)	PKLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382419	NM_000298.6(PKLR):c.965+1G>A	PKLR	Likely pathogenic	criteria provided, single submitter
225440	NM_000298.6(PKLR):c.1379T>C (p.Val460Ala)	PKLR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235407	NM_000298.6(PKLR):c.1516G>A (p.Val506Ile)	PKLR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449546	NM_000298.6(PKLR):c.1614A>T (p.Glu538Asp)	PKLR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029781	NM_000298.6(PKLR):c.1469G>A (p.Arg490Gln)	PKLR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1512	NM_000298.6(PKLR):c.110G>A (p.Gly37Glu)	PKLR	Affects	no assertion criteria provided
2444037	NM_000298.6(PKLR):c.1029G>C (p.Glu343Asp)	PKLR	Uncertain significance	criteria provided, single submitter
3382420	NM_000298.6(PKLR):c.382G>C (p.Ala128Pro)	PKLR	Uncertain significance	criteria provided, single submitter
3595349	NM_000298.6(PKLR):c.1145G>A (p.Arg382Gln)	PKLR	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PKLR	Definitive	Autosomal recessive	pyruvate kinase deficiency of red cells	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKLR	Orphanet:766	Hemolytic anemia due to red cell pyruvate kinase 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
PKLR	HGNC:9020	ENSG00000143627	P30613	Pyruvate kinase PKLR	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PKLR	Pyruvate kinase PKLR	Pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with the synthesis of ATP, and which plays a key role in glycolysis.

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)
PKLR	Kinase	yes	2.7.1.40	Pyr_Knase, Pyrv_Knase-like_insert_dom_sf, Pyrv_Knase_brl

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
duodenum	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PKLR	69	tissue_specific	marker	liver, right lobe of liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PKLR	94

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKLR	P30613	58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
ChREBP activates metabolic gene expression	1	1268.9×	0.004	PKLR
Regulation of gene expression in beta cells	1	519.1×	0.004	PKLR
Pyruvate metabolism	1	407.9×	0.004	PKLR
Glycolysis	1	285.5×	0.004	PKLR
SARS-CoV-1-host interactions	1	175.7×	0.006	PKLR

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
pyruvate biosynthetic process	1	2106.5×	0.003	PKLR
response to metal ion	1	1532.0×	0.003	PKLR
cellular response to epinephrine stimulus	1	1296.3×	0.003	PKLR
response to ATP	1	991.3×	0.003	PKLR
response to cAMP	1	510.7×	0.004	PKLR
glycolytic process	1	383.0×	0.004	PKLR
response to nutrient	1	295.6×	0.005	PKLR
response to glucose	1	255.3×	0.005	PKLR
cellular response to insulin stimulus	1	170.2×	0.007	PKLR
response to hypoxia	1	95.8×	0.010	PKLR

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PKLR	MITAPIVAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PKLR	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MITAPIVAT	4	PKLR
SURAMIN	3	PKLR
ELLAGIC ACID	2	PKLR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PKLR	82	Binding:69, Functional:12, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PKLR	2.7.1.40	pyruvate kinase

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
MITAPIVAT	4	PKLR
SURAMIN	3	PKLR
ELLAGIC ACID	2	PKLR

Druggability pyramid

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

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.