PFKL

Summary

PFKL (phosphofructokinase, liver type, HGNC:8876) is a protein-coding gene on chromosome 21q22.3, encoding ATP-dependent 6-phosphofructokinase, liver type (P17858). Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.

This gene encodes the liver (L) subunit of an enzyme that catalyzes the conversion of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate, which is a key step in glucose metabolism (glycolysis). This enzyme is a tetramer that may be composed of different subunits encoded by distinct genes in different tissues. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5211 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 163 total
• Druggable target: yes
• MANE Select transcript: NM_002626

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8876
Approved symbol	PFKL
Name	phosphofructokinase, liver type
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141959
Ensembl biotype	protein_coding
OMIM	171860
Entrez	5211

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 37 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000349048, ENST00000397961, ENST00000460020, ENST00000460521, ENST00000466134, ENST00000467315, ENST00000474114, ENST00000491298, ENST00000495274, ENST00000496824, ENST00000498841, ENST00000628044, ENST00000885165, ENST00000885166, ENST00000885167, ENST00000885168, ENST00000885169, ENST00000885170, ENST00000885171, ENST00000885172, ENST00000885173, ENST00000885174, ENST00000885175, ENST00000885176, ENST00000885177, ENST00000885178, ENST00000885179, ENST00000885180, ENST00000885181, ENST00000885182, ENST00000885183, ENST00000885184, ENST00000885185, ENST00000916368, ENST00000916369, ENST00000946328, ENST00000946329, ENST00000946330, ENST00000946331, ENST00000946332, ENST00000946333, ENST00000946334, ENST00000946335, ENST00000946336, ENST00000946337, ENST00000946338, ENST00000946339

RefSeq mRNA: 2 — MANE Select: NM_002626 NM_001002021, NM_002626

CCDS: CCDS33582

Canonical transcript exons

ENST00000349048 — 22 exons

Exon	Start	End
ENSE00003458220	44326159	44326264
ENSE00003468441	44311006	44311083
ENSE00003468758	44312105	44312294
ENSE00003470814	44319351	44319415
ENSE00003482974	44313913	44314021
ENSE00003483524	44326715	44327373
ENSE00003487259	44313638	44313682
ENSE00003492099	44324491	44324655
ENSE00003533809	44325961	44326060
ENSE00003538638	44325153	44325264
ENSE00003543348	44322962	44323049
ENSE00003556813	44306681	44306754
ENSE00003572167	44318470	44318595
ENSE00003610456	44316244	44316339
ENSE00003615543	44324856	44324917
ENSE00003620819	44312978	44313143
ENSE00003650066	44323766	44323918
ENSE00003668706	44316432	44316524
ENSE00003669897	44320084	44320147
ENSE00003682480	44321729	44321875
ENSE00003688681	44322133	44322203
ENSE00003843359	44300053	44300190

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.7687 / max 266.7608, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189459	62.6634	1823
189462	0.1053	55

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.67	gold quality
metanephros cortex	UBERON:0010533	98.42	gold quality
tibial nerve	UBERON:0001323	97.85	gold quality
transverse colon	UBERON:0001157	97.58	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.49	gold quality
right frontal lobe	UBERON:0002810	97.32	gold quality
lower esophagus mucosa	UBERON:0035834	97.26	gold quality
skin of abdomen	UBERON:0001416	97.22	gold quality
body of stomach	UBERON:0001161	97.13	gold quality
skin of leg	UBERON:0001511	97.12	gold quality
endocervix	UBERON:0000458	96.97	gold quality
right uterine tube	UBERON:0001302	96.83	gold quality
spinal cord	UBERON:0002240	96.75	gold quality
ectocervix	UBERON:0012249	96.73	gold quality
esophagus mucosa	UBERON:0002469	96.66	gold quality
granulocyte	CL:0000094	96.65	gold quality
small intestine	UBERON:0002108	96.61	gold quality
amygdala	UBERON:0001876	96.59	gold quality
right lobe of liver	UBERON:0001114	96.51	gold quality
ventricular zone	UBERON:0003053	96.46	gold quality
nucleus accumbens	UBERON:0001882	96.43	gold quality
minor salivary gland	UBERON:0001830	96.40	gold quality
mucosa of stomach	UBERON:0001199	96.33	gold quality
right lung	UBERON:0002167	96.27	gold quality
left testis	UBERON:0004533	96.24	gold quality
sural nerve	UBERON:0015488	96.18	gold quality
esophagus	UBERON:0001043	96.13	gold quality
omental fat pad	UBERON:0010414	96.13	gold quality
spleen	UBERON:0002106	96.11	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6524	no	97.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

16 targeting PFKL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-660-3P	98.14	66.04	1434

Literature-anchored findings (GeneRIF, showing 12)

• findings showed glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells (PMID:22923583)
• Liver PFK1 isoform assembles into filaments in a tetramer- and substrate-dependent manner,organizing isoform specific glucose metabolism in cells. (PMID:28646105)
• TAp73 deficiency results in a pronounced reduction in tumorigenic potential, which can be rescued by forced PFKL expression. (PMID:30409970)
• (125)I irradiation upregulated the suppression of miR-338 on PFKL to downregulate the Warburg effect. (PMID:31514072)
• A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma. (PMID:32015333)
• Biochemical and transcript level differences between the three human phosphofructokinases show optimisation of each isoform for specific metabolic niches. (PMID:33141153)
• Selective activation of PFKL suppresses the phagocytic oxidative burst. (PMID:34320407)
• Relocation of phosphofructokinases within epithelial cells is a novel event preceding breast cancer recurrence that accurately predicts patient outcomes. (PMID:34348486)
• miR-21-5p/Tiam1-mediated glycolysis reprogramming drives breast cancer progression via enhancing PFKL stabilization. (PMID:35511493)
• EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL. (PMID:38287371)
• Ubiquitin-specific protease 14 targets PFKL-mediated glycolysis to promote the proliferation and migration of oral squamous cell carcinoma. (PMID:38388430)
• Structural basis for allosteric regulation of human phosphofructokinase-1. (PMID:39183237)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pfkla	ENSDARG00000060504
danio_rerio	pfklb	ENSDARG00000099755
mus_musculus	Pfkl	ENSMUSG00000020277
rattus_norvegicus	Pfkl	ENSRNOG00000001214
drosophila_melanogaster	Pfk	FBGN0003071
caenorhabditis_elegans		WBGENE00022199

Paralogs (2): PFKP (ENSG00000067057), PFKM (ENSG00000152556)

Protein

Protein identifiers

ATP-dependent 6-phosphofructokinase, liver type — P17858 (reviewed: P17858)

Alternative names: 6-phosphofructokinase type B, Phosphofructo-1-kinase isozyme B, Phosphohexokinase

All UniProt accessions (2): P17858, F8WEU2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. Negatively regulates the phagocyte oxidative burst in response to bacterial infection by controlling cellular NADPH biosynthesis and NADPH oxidase-derived reactive oxygen species. Upon macrophage activation, drives the metabolic switch toward glycolysis, thus preventing glucose turnover that produces NADPH via pentose phosphate pathway.

Subunit / interactions. Homo- and heterotetramers. Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues.

Subcellular location. Cytoplasm.

Post-translational modifications. GlcNAcylation at Ser-529 by OGT decreases enzyme activity, leading to redirect glucose flux through the oxidative pentose phosphate pathway. Glycosylation is stimulated by both hypoxia and glucose deprivation.

Activity regulation. Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate. GlcNAcylation by OGT overcomes allosteric regulation.

Pathway. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 3/4.

Miscellaneous. In human PFK exists as a system of 3 types of subunits, PFKM (muscle), PFKL (liver) and PFKP (platelet) isoenzymes. Glycosylation may play a role in cancer cell proliferation: inhibition of 6-phosphofructokinase activity and subsequent redirection of the glucose flux through the oxidative pentose phosphate pathway confers a selective growth advantage on cancer cells. Moreover GlcNAcylation is observed in multiple cancer cell lines and tissue samples and GlcNAcylation leads to larger xenografts tunors in mice.

Similarity. Belongs to the phosphofructokinase type A (PFKA) family. ATP-dependent PFK group I subfamily. Eukaryotic two domain clade ‘E’ sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P17858-1	1	yes
P17858-2	2, a

RefSeq proteins (2): NP_001002021, NP_002617* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000023	Phosphofructokinase_dom	Domain
IPR009161	6-Pfructokinase_euk	Family
IPR015912	Phosphofructokinase_CS	Conserved_site
IPR022953	ATP_PFK	Family
IPR035966	PKF_sf	Homologous_superfamily
IPR041914	PFK_vert-type	Family

Pfam: PF00365

Enzyme classification (BRENDA):

• EC 2.7.1.11 — 6-phosphofructokinase (BRENDA: 98 organisms, 152 substrates, 280 inhibitors, 278 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

22 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.005–0.82	125
D-FRUCTOSE 6-PHOSPHATE	0.007–254	69
GTP	0.0006–4.3	9
CTP	0.018–11	8
UTP	0.009–5.1	8
ITP	0.003–2.2	6
ADP	0.32–1.4	5
FRUCTOSE 6-PHOSPHATE	0.01–0.2	4
D-FRUCTOSE 1,6-BISPHOSPHATE	0.7–16.7	3
MG2+	0.01–0.025	2
2-DEHYDRO-3-DEOXY-D-GLUCONATE	8.8	1
ADENOSINE	1	1
AMP	1.57	1
D-GLUCOSE	90	1
D-GLUCOSE 6-PHOSPHATE	0.6	1

Catalyzed reactions (Rhea), 1 shown:

• beta-D-fructose 6-phosphate + ATP = beta-D-fructose 1,6-bisphosphate + ADP + H(+) (RHEA:16109)

UniProt features (114 total): helix 36, strand 26, binding site 18, sequence conflict 9, turn 8, modified residue 4, region of interest 3, sequence variant 3, mutagenesis site 2, initiator methionine 1, chain 1, glycosylation site 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8W2H	ELECTRON MICROSCOPY	2.6
7LW1	ELECTRON MICROSCOPY	2.9
8W2G	ELECTRON MICROSCOPY	3
8W2J	ELECTRON MICROSCOPY	3.1
8W2I	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17858-F1	92.53	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 166 (proton acceptor)

Ligand- & substrate-binding residues (18): 164–166 (in other chain); 201; 208–210 (in other chain); 264 (in other chain); 292; 298–301 (in other chain); 470 (in other chain); 527–531 (in other chain); 565; 572–574 (in other chain); 628 (in other chain); 654 …

Post-translational modifications (4): 2, 377, 640, 775

Glycosylation sites (1): 529

Mutagenesis-validated functional residues (2):

Position	Phenotype
527	does not affect glcnacylation.
529	prevents glcnacylation and enhance enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-70171	Glycolysis

MSigDB gene sets: 261 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM, HARRIS_HYPOXIA, GOCC_SECRETORY_GRANULE, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PEPTIDE_SECRETION, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_HORMONE_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP

GO Biological Process (7): fructose 6-phosphate metabolic process (GO:0006002), glycolytic process (GO:0006096), response to glucose (GO:0009749), fructose 1,6-bisphosphate metabolic process (GO:0030388), negative regulation of insulin secretion (GO:0046676), canonical glycolysis (GO:0061621), glycolytic process through fructose-6-phosphate (GO:0061615)

GO Molecular Function (13): 6-phosphofructokinase activity (GO:0003872), ATP binding (GO:0005524), kinase binding (GO:0019900), identical protein binding (GO:0042802), metal ion binding (GO:0046872), fructose binding (GO:0070061), fructose-6-phosphate binding (GO:0070095), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), monosaccharide binding (GO:0048029)

GO Cellular Component (8): extracellular region (GO:0005576), cytosol (GO:0005829), 6-phosphofructokinase complex (GO:0005945), membrane (GO:0016020), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Glucose metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
organophosphate metabolic process	2
carbohydrate derivative metabolic process	2
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
response to hexose	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
6-phosphofructokinase activity	1
fructose-bisphosphate aldolase activity	1
triose-phosphate isomerase activity	1
glycolytic process	1
phosphofructokinase activity	1
glycolytic process through fructose-6-phosphate	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
enzyme binding	1
protein binding	1
cation binding	1
monosaccharide binding	1
anion binding	1
carbohydrate derivative binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFKL	ALDOA	P04075	867
PFKL	J3KPS3	J3KPS3	852
PFKL	PWP2	Q15269	803
PFKL	ALDOB	P05062	796
PFKL	HK1	P19367	753
PFKL	PKM	P14618	741
PFKL	TPI1	P00938	728
PFKL	PGK1	P00558	724
PFKL	ENO1	P06733	719
PFKL	PFKM	P08237	716
PFKL	PKLR	P11973	711
PFKL	LDHA	P00338	707
PFKL	COL6A1	P12109	698
PFKL	ALDOC	P09972	676
PFKL	PGAM4	Q8N0Y7	676

IntAct

131 interactions, top by confidence:

A	B	Type	Score
FOXP4	FOXP2	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PFKL	PFKL	psi-mi:“MI:0915”(physical association)	0.570
PFKM	PFKL	psi-mi:“MI:0915”(physical association)	0.570
PFKL	PFKM	psi-mi:“MI:0915”(physical association)	0.570
PFKL	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
PFKL	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	PFKL	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	PFKL	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	PFKL	psi-mi:“MI:0915”(physical association)	0.560
PFKL	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (283): PFKL (Affinity Capture-MS), PFKL (Two-hybrid), PFKL (Two-hybrid), GTPBP3 (Two-hybrid), KRTAP10-7 (Two-hybrid), PFKL (Affinity Capture-MS), PFKL (Affinity Capture-MS), PFKL (Affinity Capture-MS), PFKL (Affinity Capture-MS), PFKL (Affinity Capture-MS), KRTAP4-12 (Two-hybrid), APEH (Co-fractionation), PFKL (Co-fractionation), PFKL (Co-fractionation), PFKL (Co-fractionation)

ESM2 similar proteins: A1A4J1, A2E9H3, A2EF58, C4QXA5, O42938, O61068, O83146, O94200, O94201, P00511, P08237, P12382, P16862, P17858, P30835, P47857, P47858, P47859, P47860, P51553, P52034, P52784, P59680, P78985, Q01813, Q03216, Q0IIG5, Q27483, Q27665, Q27705, Q27778, Q2HYU2, Q2RNU4, Q4W9B8, Q5R636, Q5R7V5, Q5RAG9, Q60HD9, Q867C9, Q8TGA0

Diamond homologs: A0PYC8, A0RJJ6, A1A4J1, A5I798, A5IKL2, A6TVD3, A7FYW7, A7GIW9, A7GTP4, A7Z7K6, A8FG55, A8MLY0, A9VJR1, B0K6L2, B0K7U7, B1IFV9, B1L266, B1L9U3, B2A6Y0, B7GGT1, B7HFB3, B7HRN9, B7IJZ8, B7JRX2, B8D1K5, B9DN94, B9J099, B9K6R9, C0Z7W7, C1EUU3, C1FM55, C3KV06, C3L8X8, C3PAI8, C4K7E1, C4LEQ5, C4QXA5, C5D663, O34529, O42938

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PFKL	“down-regulates quantity”	“β-D-fructose 6-phosphate”	“chemical modification”
PFKL	“up-regulates quantity”	“beta-D-fructofuranose 1,6-bisphosphate(4-)”	“chemical modification”
“beta-D-fructofuranose 2,6-bisphosphate”	“up-regulates activity”	PFKL	binding
OGT	“down-regulates activity”	PFKL	glycosylation
OGA	“up-regulates activity”	PFKL	deglycosylation
CyclinD3/CDK6	“down-regulates activity”	PFKL	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	5	20.2×	2e-03
canonical NF-kappaB signal transduction	5	17.6×	3e-03
cell surface receptor protein tyrosine kinase signaling pathway	8	13.4×	2e-04
positive regulation of MAPK cascade	8	6.2×	9e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	6.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

163 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	97
Likely benign	18
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

4637 predictions. Top by Δscore:

Variant	Effect	Δscore
21:44300187:CAAG:C	donor_loss	1.0000
21:44300188:AAG:A	donor_loss	1.0000
21:44300189:AGGTG:A	donor_loss	1.0000
21:44306675:CCACA:C	acceptor_loss	1.0000
21:44306676:CACA:C	acceptor_loss	1.0000
21:44306677:ACAGG:A	acceptor_loss	1.0000
21:44306678:CAGG:C	acceptor_loss	1.0000
21:44306679:A:G	acceptor_loss	1.0000
21:44306680:GGCAT:G	acceptor_gain	1.0000
21:44306755:GT:G	donor_loss	1.0000
21:44312101:GCAGG:G	acceptor_loss	1.0000
21:44312102:CA:C	acceptor_loss	1.0000
21:44312103:A:AG	acceptor_gain	1.0000
21:44312103:AG:A	acceptor_gain	1.0000
21:44312103:AGGGC:A	acceptor_gain	1.0000
21:44312104:G:GG	acceptor_gain	1.0000
21:44312104:GG:G	acceptor_gain	1.0000
21:44312104:GGGC:G	acceptor_gain	1.0000
21:44312104:GGGCG:G	acceptor_gain	1.0000
21:44312293:AG:A	donor_loss	1.0000
21:44312294:GGT:G	donor_loss	1.0000
21:44312295:G:A	donor_loss	1.0000
21:44312296:T:A	donor_loss	1.0000
21:44313139:CAGAG:C	donor_gain	1.0000
21:44313140:AGAG:A	donor_gain	1.0000
21:44313141:GAG:G	donor_gain	1.0000
21:44313141:GAGG:G	donor_gain	1.0000
21:44313144:G:GG	donor_gain	1.0000
21:44313633:CACA:C	acceptor_loss	1.0000
21:44313635:C:G	acceptor_gain	1.0000

AlphaMissense

5089 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:44313047:A:T	D166V	1.000
21:44313053:A:C	D168A	1.000
21:44313053:A:T	D168V	1.000
21:44313137:C:A	A196D	1.000
21:44313651:T:C	F203L	1.000
21:44313653:C:A	F203L	1.000
21:44313653:C:G	F203L	1.000
21:44316482:C:A	H298Q	1.000
21:44316482:C:G	H298Q	1.000
21:44316517:G:C	R310P	1.000
21:44323858:C:A	N530K	1.000
21:44323858:C:G	N530K	1.000
21:44323861:C:A	N531K	1.000
21:44323861:C:G	N531K	1.000
21:44324539:T:C	F567L	1.000
21:44324541:C:A	F567L	1.000
21:44324541:C:G	F567L	1.000
21:44325200:T:C	L642P	1.000
21:44300172:A:C	S23R	0.999
21:44300174:C:A	S23R	0.999
21:44300174:C:G	S23R	0.999
21:44300190:G:C	G29R	0.999
21:44306681:G:A	G29D	0.999
21:44306688:C:A	N31K	0.999
21:44306688:C:G	N31K	0.999
21:44306696:T:A	V34D	0.999
21:44306711:G:C	R39P	0.999
21:44312228:A:C	S121R	0.999
21:44312230:C:A	S121R	0.999
21:44312230:C:G	S121R	0.999

dbSNP variants (sampled 300 via entrez): RS1000081008 (21:44298947 T>A), RS1000209015 (21:44319103 C>CCTGGAG), RS1000403385 (21:44316350 G>A), RS1000418204 (21:44317191 G>A), RS1000422575 (21:44320671 G>A), RS1000505436 (21:44326907 C>T), RS1000648597 (21:44303084 A>G), RS1000882853 (21:44314387 C>T), RS1000913806 (21:44314576 C>T), RS1000998139 (21:44306099 T>C), RS1001060090 (21:44306221 T>C), RS1001084964 (21:44307896 A>G), RS1001186778 (21:44326479 G>T), RS1001340944 (21:44323108 C>A,T), RS1001465942 (21:44308345 T>G)

Disease associations

OMIM: gene MIM:171860 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001042_3	Rheumatoid arthritis	4.000000e-09
GCST010083_24	Hemoglobin levels	1.000000e-08
GCST90002383_101	Hematocrit	1.000000e-12
GCST90002384_495	Hemoglobin	8.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2191 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.47	Kd	33.81	nM	CHEMBL5653589
7.47	ED50	33.81	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148982: Binding affinity to human PFKL incubated for 45 mins by Kinobead based pull down assay	kd	0.0338	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
bisphenol A	affects expression, decreases methylation, increases expression	3
Smoke	increases expression, decreases expression, increases abundance	3
ochratoxin A	decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
PF-06840003	decreases expression, decreases reaction	1
quinone	increases expression, affects cotreatment	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	decreases expression, increases expression	1
yessotoxin	increases expression	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
PP242	increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118780	Binding	Binding affinity to PFKL in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.