PDXK

Summary

PDXK (pyridoxal kinase, HGNC:8819) is a protein-coding gene on chromosome 21q22.3, encoding Pyridoxal kinase (O00764). Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5’-phosphate (PLP), pyridoxine 5’-phosphate (PNP) and pyridoxamine 5’-phosphate (PMP), respectively.

The protein encoded by this gene phosphorylates vitamin B6, a step required for the conversion of vitamin B6 to pyridoxal-5-phosphate, an important cofactor in intermediary metabolism. The encoded protein is cytoplasmic and probably acts as a homodimer. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 8566 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuropathy, hereditary motor and sensory, type VIc, with optic atrophy (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 101 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003681

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8819
Approved symbol	PDXK
Name	pyridoxal kinase
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PNK, PKH, FLJ21324, PRED79, FLJ31940, MGC15873
Ensembl gene	ENSG00000160209
Ensembl biotype	protein_coding
OMIM	179020
Entrez	8566

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 13 protein_coding_CDS_not_defined, 12 protein_coding

ENST00000291565, ENST00000327574, ENST00000343528, ENST00000398078, ENST00000398081, ENST00000398085, ENST00000438837, ENST00000461123, ENST00000467908, ENST00000468090, ENST00000468392, ENST00000470029, ENST00000472777, ENST00000476084, ENST00000476313, ENST00000481512, ENST00000490666, ENST00000498040, ENST00000621478, ENST00000867731, ENST00000867732, ENST00000867733, ENST00000933237, ENST00000933238, ENST00000941196

RefSeq mRNA: 2 — MANE Select: NM_003681 NM_001331030, NM_003681

CCDS: CCDS13699, CCDS82679

Canonical transcript exons

ENST00000291565 — 11 exons

Exon	Start	End
ENSE00001861574	43719129	43719381
ENSE00003489627	43750500	43750545
ENSE00003511412	43743724	43743807
ENSE00003534315	43748995	43749080
ENSE00003552597	43753583	43753719
ENSE00003583352	43752518	43752629
ENSE00003585237	43734069	43734123
ENSE00003647981	43755698	43755764
ENSE00003670847	43741667	43741771
ENSE00003694032	43746079	43746125
ENSE00003849330	43755951	43762299

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 92.9692 / max 1145.3604, expressed in 1828 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189377	87.4126	1828
189389	1.5394	929
189381	1.1449	492
189380	1.0233	408
189388	0.5172	244
189384	0.4177	5
189379	0.2577	124
189382	0.2364	53
189383	0.2130	103
189376	0.0898	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.63	gold quality
right testis	UBERON:0004534	99.57	gold quality
adult organism	UBERON:0007023	98.31	gold quality
sperm	CL:0000019	98.25	gold quality
renal medulla	UBERON:0000362	98.07	gold quality
male germ cell	CL:0000015	97.96	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.77	gold quality
adenohypophysis	UBERON:0002196	97.48	gold quality
testis	UBERON:0000473	97.32	gold quality
pituitary gland	UBERON:0000007	97.18	gold quality
metanephros cortex	UBERON:0010533	96.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.84	gold quality
right frontal lobe	UBERON:0002810	96.75	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.74	gold quality
nucleus accumbens	UBERON:0001882	96.73	gold quality
postcentral gyrus	UBERON:0002581	96.73	gold quality
parietal lobe	UBERON:0001872	96.67	gold quality
CA1 field of hippocampus	UBERON:0003881	96.63	gold quality
minor salivary gland	UBERON:0001830	96.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.59	gold quality
inferior olivary complex	UBERON:0002127	96.57	gold quality
amygdala	UBERON:0001876	96.31	gold quality
apex of heart	UBERON:0002098	96.27	gold quality
putamen	UBERON:0001874	96.16	gold quality
superior frontal gyrus	UBERON:0002661	96.15	gold quality
body of pancreas	UBERON:0001150	96.14	gold quality
temporal lobe	UBERON:0001871	96.13	gold quality
mouth mucosa	UBERON:0003729	96.13	gold quality
upper lobe of left lung	UBERON:0008952	96.13	gold quality
entorhinal cortex	UBERON:0002728	96.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.25
E-HCAD-13	yes	7.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F4

miRNA regulators (miRDB)

199 targeting PDXK, 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-4673	100.00	66.64	1490
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505

Literature-anchored findings (GeneRIF, showing 9)

• Pyridoxal kinase expression was compared in fetal Down syndrome (DS) brain and controls; PDXK levels were found to be similar. (PMID:15082224)
• A promoter mutation with potential erythroid-specific properties that could be the basis of a novel mechanism of controlling cell-specific decreased activity of an essential enzyme in erythrocytes. (PMID:16704963)
• The crystal structure of the MgATP complex also reveals Mg(2+) and Na(+) acting in tandem to anchor the ATP at the active site of pyridoxal kinase. (PMID:17766369)
• These results document the role of Asp235 in PL kinase activity. (PMID:19351586)
• This study identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort This association was confirmed in the British and Italian cohorts individually and reached a combined value. (PMID:20035503)
• The pyridoxal kinase showed decreased levels and was highly carbonylated in the gene-on mice (PMID:20639122)
• The affected pyridoxine metabolism is discussed as an inborn genetic trait in epilepsy in general, rather than a specific sign of pyridoxine-dependent epilepsy solely. (PMID:22647618)
• The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity. (PMID:31578392)
• [Pyridoxal kinase (PDXK) promotes the proliferation of serous ovarian cancer cells and is associated with poor prognosis]. (PMID:32696745)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdxkb	ENSDARG00000036546
danio_rerio	pdxka	ENSDARG00000088959
mus_musculus	Pdxk	ENSMUSG00000032788
rattus_norvegicus	Pdxk	ENSRNOG00000049937
rattus_norvegicus	Pdxkl1	ENSRNOG00000068407
drosophila_melanogaster	Pdxk	FBGN0085484
caenorhabditis_elegans	pdxk-1	WBGENE00019008

Protein

Protein identifiers

Pyridoxal kinase — O00764 (reviewed: O00764)

Alternative names: Pyridoxine kinase

All UniProt accessions (6): O00764, A0A0B4J2C9, A8MT14, A8MV33, F2Z2Y4, V9HWC3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5’-phosphate (PLP), pyridoxine 5’-phosphate (PNP) and pyridoxamine 5’-phosphate (PMP), respectively. PLP is the active form of vitamin B6, and acts as a cofactor for over 140 different enzymatic reactions.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous. Highly expressed in testis. In adult testis and spermatozoa.

Disease relevance. Neuropathy, hereditary motor and sensory, 6C, with optic atrophy (HMSN6C) [MIM:618511] An autosomal recessive neurologic disorder characterized by childhood onset of axonal, sensorimotor polyneuropathy affecting mainly the lower limbs, and adult-onset optic atrophy. Clinical features include progressive distal muscle weakness and atrophy, significant standing and walking difficulties, areflexia, neurogenic pain and progressive visual impairment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Catalytic activity is inhibited competitively by 4-deoxypyridoxine, and is also inhibited by the benzodiazepine receptor ligands 1012S and ethyl-beta-carboline-3-carboxylate. Inhibited by ginkgotoxin, theophylline, lamotrigine, enprofylline, theobromine, and caffeine. Activity is increased in the presence of K(+)or Na(+).

Cofactor. Zn(2+) is the most effective divalent metal cation in vitro, followed by Co(2+), Mn(2+) and Mg(2+).

Induction. Transcriptionally regulated by Sp1 transcription factor.

Pathway. Cofactor metabolism; pyridoxal 5’-phosphate salvage; pyridoxal 5’-phosphate from pyridoxal: step 1/1. Cofactor metabolism; pyridoxal 5’-phosphate salvage; pyridoxine 5’-phosphate from pyridoxine: step 1/1. Cofactor metabolism; pyridoxal 5’-phosphate salvage; pyridoxamine 5’-phosphate from pyridoxamine: step 1/1.

Similarity. Belongs to the pyridoxine kinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O00764-1	1	yes
O00764-2	2
O00764-3	3, PKH-T

RefSeq proteins (2): NP_001317959, NP_003672* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004625	PyrdxlKinase	Family
IPR013749	PM/HMP-P_kinase-1	Domain
IPR029056	Ribokinase-like	Homologous_superfamily

Pfam: PF08543

Enzyme classification (BRENDA):

• EC 2.7.1.35 — pyridoxal kinase (BRENDA: 31 organisms, 59 substrates, 123 inhibitors, 121 Km, 69 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PYRIDOXAL	0.0012–3.839	42
ATP	0.0091–3.096	40
PYRIDOXINE	0.0017–2.07	17
PYRIDOXAMINE	0.006–0.1818	10
4-AMINO-5-HYDROXYMETHYL-2-METHYLPYRIMIDINE	1.85–2.03	3
GINKGOTOXIN	0.005–0.0466	3
4’-DEOXYPYRIDOXINE	0.0216	2
4’-O-METHYLPYRIDOXINE	0.005	1

Catalyzed reactions (Rhea), 3 shown:

• pyridoxal + ATP = pyridoxal 5’-phosphate + ADP + H(+) (RHEA:10224)
• pyridoxamine + ATP = pyridoxamine 5’-phosphate + ADP + H(+) (RHEA:25104)
• pyridoxine + ATP = pyridoxine 5’-phosphate + ADP + H(+) (RHEA:25108)

UniProt features (52 total): binding site 13, strand 13, helix 11, modified residue 5, splice variant 2, sequence variant 2, mutagenesis site 2, turn 2, chain 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8WR2	X-RAY DIFFRACTION	1.94
2YXT	X-RAY DIFFRACTION	2
3KEU	X-RAY DIFFRACTION	2.1
4EOH	X-RAY DIFFRACTION	2.1
4EN4	X-RAY DIFFRACTION	2.15
2YXU	X-RAY DIFFRACTION	2.2
3FHY	X-RAY DIFFRACTION	2.3
2AJP	X-RAY DIFFRACTION	2.5
3FHX	X-RAY DIFFRACTION	2.5
2F7K	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00764-F1	95.83	0.92

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): 235 (proton acceptor)

Ligand- & substrate-binding residues (13): 186–187; 186; 226–228; 233; 234–235; 12; 47; 47; 113; 113; 118; 148 …

Post-translational modifications (5): 1, 59, 164, 213, 285

Mutagenesis-validated functional residues (2):

Position	Phenotype
235	15-fold decrease in pyridoxal kinase activity, and a 7-fold decrease in affinity for pyridoxal.
235	2-fold decrease in pyridoxal kinase activity and pyridoxal affinity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-964975	Vitamin B6 activation to pyridoxal phosphate

MSigDB gene sets: 398 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, CCTGTGA_MIR513, GOBP_VITAMIN_BIOSYNTHETIC_PROCESS, DER_IFN_BETA_RESPONSE_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_ALDEHYDE_METABOLIC_PROCESS

GO Biological Process (5): pyridoxal 5’-phosphate salvage (GO:0009443), pyridoxal metabolic process (GO:0042817), pyridoxamine metabolic process (GO:0042818), vitamin B6 metabolic process (GO:0042816), pyridoxal 5’-phosphate metabolic process (GO:0042822)

GO Molecular Function (14): magnesium ion binding (GO:0000287), ATP binding (GO:0005524), zinc ion binding (GO:0008270), pyridoxal kinase activity (GO:0008478), pyridoxal phosphate binding (GO:0030170), potassium ion binding (GO:0030955), sodium ion binding (GO:0031402), lithium ion binding (GO:0031403), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773), metal ion binding (GO:0046872)

GO Cellular Component (8): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), secretory granule lumen (GO:0034774), specific granule lumen (GO:0035580), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vitamin B6 metabolic process	3
alkali metal ion binding	3
aldehyde metabolic process	2
transferase activity, transferring phosphorus-containing groups	2
pyridoxal 5’-phosphate biosynthetic process	1
metabolic compound salvage	1
vitamin metabolic process	1
pyridine-containing compound metabolic process	1
organophosphate metabolic process	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
anion binding	1
vitamin B6 binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
secretory granule	1
cytoplasmic vesicle lumen	1
secretory granule lumen	1
specific granule	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1801 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDXK	PNPO	Q9NVS9	845
PDXK	TEF	Q10587	832
PDXK	DBP	Q10586	714
PDXK	PDXP	Q96GD0	670
PDXK	RRP1B	Q14684	632
PDXK	PLPBP	O94903	606
PDXK	TRAPPC4	Q9Y296	576
PDXK	ZBTB21	Q9ULJ3	530
PDXK	AKR1B1	P15121	496
PDXK	P0DN79	P0DN79	489
PDXK	EVA1C	P58658	489
PDXK	H7C2H4	H7C2H4	488
PDXK	SHMT1	P34896	467
PDXK	RBKS	Q9H477	465
PDXK	DONSON	Q9NYP3	464

IntAct

21 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
PDXK	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
PARP12	PDXK	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
MAP1LC3A		psi-mi:“MI:0914”(association)	0.350
MAP1LC3B		psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
HLA-A	AIP	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
VCP	SHTN1	psi-mi:“MI:0914”(association)	0.350
	MYO1C	psi-mi:“MI:0914”(association)	0.350
PRKAB1	PDXK	psi-mi:“MI:0915”(physical association)	0.000
IKBKE	PDXK	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (77): PDXK (Affinity Capture-RNA), PDXK (Affinity Capture-RNA), ABAT (Co-fractionation), OGT (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), PDXK (Co-fractionation), RABIF (Co-fractionation)

ESM2 similar proteins: A1L1L6, B1H369, B1WC68, O00764, O35331, O46560, O54956, O95803, P10155, P38024, P52848, P56965, P58710, P81799, P82197, Q02353, Q0II59, Q0VCB2, Q2HJF8, Q2QNG7, Q3SZM9, Q3U129, Q3UHN9, Q4R4U1, Q5R5F8, Q5U4X8, Q5ZM83, Q6GPA7, Q6GQK9, Q6GV29, Q6NVC5, Q7SXM0, Q80YV4, Q8BG51, Q8IXI2, Q8K183, Q8VH37, Q91WA3, Q923S8, Q969T7

Diamond homologs: A1A6H3, A3N2D3, A5UA83, A5WB73, A6VEZ4, A6VNE5, A7N5Q6, B0KR83, B0UUD2, B1JFM7, B2JCI0, B3H2H2, B7V753, C3K4G7, O00764, O01824, O14242, O35331, O46560, O74860, P0A9J6, P0A9J7, P39988, P44690, P53727, P77150, P82197, Q02DJ3, Q0BSF0, Q0I3D2, Q0II59, Q0THJ1, Q141E8, Q1AYE5, Q1BXQ7, Q1C792, Q1CIM6, Q1I2L8, Q1J237, Q1LFU5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Macroautophagy	6	36.4×	2e-06
Neddylation	5	12.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	70.2×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	32
Likely benign	12
Benign	26

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2652725	NM_003681.5(PDXK):c.465-15_489delinsGCA	Pathogenic
636264	NM_003681.5(PDXK):c.682G>A (p.Ala228Thr)	Pathogenic
636265	NM_003681.5(PDXK):c.659G>A (p.Arg220Gln)	Pathogenic
830405	NC_000021.8:g.(?44836602)(45629566_?)del	Pathogenic
812519	NM_003681.5(PDXK):c.225T>A (p.Asn75Lys)	Likely pathogenic

SpliceAI

2652 predictions. Top by Δscore:

Variant	Effect	Δscore
21:43719380:AGGT:A	donor_loss	1.0000
21:43719382:G:C	donor_loss	1.0000
21:43719383:T:G	donor_loss	1.0000
21:43734063:TTGCA:T	acceptor_loss	1.0000
21:43734064:TGCA:T	acceptor_loss	1.0000
21:43734065:GCAG:G	acceptor_loss	1.0000
21:43734066:CAG:C	acceptor_loss	1.0000
21:43734067:AGGT:A	acceptor_loss	1.0000
21:43734068:G:A	acceptor_loss	1.0000
21:43734120:ACAGG:A	donor_loss	1.0000
21:43734122:AGG:A	donor_loss	1.0000
21:43734124:G:GC	donor_loss	1.0000
21:43741772:GTA:G	donor_loss	1.0000
21:43746077:A:AG	acceptor_gain	1.0000
21:43746078:G:GG	acceptor_gain	1.0000
21:43746078:GT:G	acceptor_gain	1.0000
21:43746078:GTGT:G	acceptor_gain	1.0000
21:43748985:T:A	acceptor_gain	1.0000
21:43748988:T:TA	acceptor_gain	1.0000
21:43748989:G:A	acceptor_gain	1.0000
21:43748993:A:AG	acceptor_gain	1.0000
21:43748994:G:GA	acceptor_gain	1.0000
21:43748994:GTAC:G	acceptor_gain	1.0000
21:43749076:GCCGA:G	donor_gain	1.0000
21:43749077:CCGA:C	donor_gain	1.0000
21:43749078:CGA:C	donor_gain	1.0000
21:43749078:CGAGT:C	donor_loss	1.0000
21:43749079:GA:G	donor_gain	1.0000
21:43749079:GAG:G	donor_gain	1.0000
21:43749079:GAGT:G	donor_loss	1.0000

AlphaMissense

2059 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:43753664:A:C	D235A	0.996
21:43753664:A:T	D235V	0.996
21:43749075:G:C	E153D	0.995
21:43749075:G:T	E153D	0.995
21:43749076:G:C	A154P	0.995
21:43752558:T:A	V184D	0.995
21:43753664:A:G	D235G	0.995
21:43753665:C:A	D235E	0.995
21:43753665:C:G	D235E	0.995
21:43719328:A:C	S12R	0.994
21:43719330:C:A	S12R	0.994
21:43719330:C:G	S12R	0.994
21:43719353:G:A	G20D	0.994
21:43753663:G:C	D235H	0.994
21:43719329:G:T	S12I	0.993
21:43719353:G:T	G20V	0.993
21:43719343:G:C	G17R	0.992
21:43719352:G:C	G20R	0.992
21:43734109:T:C	F43S	0.992
21:43749062:C:A	P149H	0.992
21:43746081:T:C	C112R	0.991
21:43746083:T:G	C112W	0.991
21:43746085:A:G	D113G	0.991
21:43749047:C:A	A144E	0.991
21:43752555:T:A	V183E	0.991
21:43752566:A:C	S187R	0.991
21:43752568:C:A	S187R	0.991
21:43752568:C:G	S187R	0.991
21:43753648:T:C	F230L	0.991
21:43753650:T:A	F230L	0.991

dbSNP variants (sampled 300 via entrez): RS1000000157 (21:43741982 T>C), RS1000003194 (21:43717222 G>A,T), RS1000042038 (21:43738696 G>C), RS1000157986 (21:43733535 T>A,C), RS1000210594 (21:43753154 G>A), RS1000234067 (21:43718590 C>T), RS1000280438 (21:43719816 C>T), RS1000297224 (21:43752215 G>A), RS1000300026 (21:43748287 T>C), RS1000332277 (21:43720046 G>C), RS1000351765 (21:43748007 C>T), RS1000365118 (21:43750473 A>C), RS1000533459 (21:43760620 T>C), RS1000545629 (21:43755643 G>A), RS1000571479 (21:43717380 C>T)

Disease associations

OMIM: gene MIM:179020 | disease phenotypes: MIM:618511, MIM:616341, MIM:254800

GenCC curated gene-disease

Disease	Classification	Inheritance
neuropathy, hereditary motor and sensory, type VIc, with optic atrophy	Strong	Autosomal recessive

Mondo (3): neuropathy, hereditary motor and sensory, type VIc, with optic atrophy (MONDO:0032792), developmental and epileptic encephalopathy, 30 (MONDO:0014595), progressive myoclonus epilepsy (MONDO:0020074)

Orphanet (2): Progressive myoclonic epilepsy type 1 (Orphanet:308), Progressive myoclonic epilepsy (Orphanet:98261)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000648	Optic atrophy
HP:0001284	Areflexia
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002403	Positive Romberg sign
HP:0003484	Upper limb muscle weakness
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0006886	Impaired distal vibration sensation
HP:0007210	Lower limb amyotrophy
HP:0007328	Impaired pain sensation
HP:0007340	Lower limb muscle weakness
HP:0007663	Reduced visual acuity
HP:0011463	Childhood onset
HP:0034337	Claw hand deformity

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003825_4	Systolic blood pressure change trajectory	7.000000e-07
GCST003825_7	Systolic blood pressure change trajectory	1.000000e-06
GCST006585_2849	Blood protein levels	5.000000e-09
GCST010002_77	Refractive error	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006944	systolic blood pressure change measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075181 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 84,842 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL535	SUNITINIB	4	79,020
CHEMBL1233528	VOLASERTIB	3	1,511
CHEMBL2220486	LUCITANIB	2	1,150
CHEMBL230011	TG100-115	2	1,504
CHEMBL3907479	FGFR INHIBITOR DEBIO 1347	2	762
CHEMBL513909	BI-2536	2	895

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 13 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.29	Kd	5.092	nM	CHEMBL3752910
8.29	ED50	5.092	nM	CHEMBL3752910
6.54	Kd	286	nM	VOLASERTIB
6.41	Kd	387	nM	BI-2536
5.92	Kd	1195	nM	CHEMBL5653589
5.92	ED50	1195	nM	CHEMBL5653589
5.68	Kd	2110	nM	FGFR INHIBITOR DEBIO 1347
5.28	Kd	5251	nM	TG100-115
5.22	Kd	6021	nM	SUNITINIB

PubChem BioAssay actives

8 with measured affinity, of 273 total; 8 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148973: Binding affinity to human PDXK incubated for 45 mins by Kinobead based pull down assay	kd	0.0051	uM
N-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-4-[[(7R)-7-ethyl-5-methyl-6-oxo-8-propan-2-yl-7H-pteridin-2-yl]amino]-3-methoxybenzamide	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2860	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.3870	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148973: Binding affinity to human PDXK incubated for 45 mins by Kinobead based pull down assay	kd	1.1949	uM
[5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.1100	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	5.2510	uM
Sunitinib	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	6.0210	uM
6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide	1425106: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	16.4040	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	decreases methylation, increases expression, affects cotreatment, decreases expression	3
bisphenol A	decreases expression, decreases methylation, affects cotreatment	3
Cadmium Chloride	increases expression	3
sodium arsenite	affects expression, decreases expression, increases abundance	2
bisphenol S	decreases methylation, increases expression	2
Smoke	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	affects expression, increases methylation	2
Metribolone	affects splicing, decreases expression	2
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenate	increases expression	1
decabromobiphenyl ether	decreases expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	increases expression	1
pyridoxal phosphate gamma-aminobutyric acid	decreases reaction, increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1

ChEMBL screening assays

21 unique, capped per target: 20 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1116771	Binding	Activity at human PKH kinase expressed in Escherichia coli by affinity chromatography	Ginkgo biloba and ginkgotoxin. — J Nat Prod
CHEMBL3821394	ADMET	Binding affinity to PDXK in human HepG2 assessed as intensity fold change of cumulated normalized intensity of protein between capture and competition assay at 100 uM after 1 hr in presence of inactive Tcp-CC 14 by differential competition	Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3DP	Abcam HEK293T PDXK KO	Transformed cell line	Female
CVCL_TC88	HAP1 PDXK (-) 1	Cancer cell line	Male
CVCL_XR51	HAP1 PDXK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06593951	Not specified	RECRUITING	Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)
NCT06923241	Not specified	COMPLETED	Nutri-score Labelling in a UK Restaurant Setting: a Randomised Control Trial