PNPO

Summary

PNPO (pyridoxamine 5’-phosphate oxidase, HGNC:30260) is a protein-coding gene on chromosome 17q21.32, encoding Pyridoxine-5’-phosphate oxidase (Q9NVS9). Catalyzes the oxidation of either pyridoxine 5’-phosphate (PNP) or pyridoxamine 5’-phosphate (PMP) into pyridoxal 5’-phosphate (PLP).

The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5’-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5’-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy.

Source: NCBI Gene 55163 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyridoxal phosphate-responsive seizures (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 402 total — 21 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• MANE Select transcript: NM_018129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30260
Approved symbol	PNPO
Name	pyridoxamine 5’-phosphate oxidase
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	PDXPO
Ensembl gene	ENSG00000108439
Ensembl biotype	protein_coding
OMIM	603287
Entrez	55163

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000225573, ENST00000434554, ENST00000582171, ENST00000583245, ENST00000583599, ENST00000584061, ENST00000584806, ENST00000585320, ENST00000641285, ENST00000641305, ENST00000641323, ENST00000641427, ENST00000641511, ENST00000641703, ENST00000641709, ENST00000641856, ENST00000642017, ENST00000958513, ENST00000958514

RefSeq mRNA: 1 — MANE Select: NM_018129 NM_018129

CCDS: CCDS11522

Canonical transcript exons

ENST00000642017 — 7 exons

Exon	Start	End
ENSE00003482418	47946323	47946393
ENSE00003510934	47943306	47943430
ENSE00003585486	47944616	47944715
ENSE00003679517	47945559	47945612
ENSE00003686649	47945861	47945989
ENSE00003813015	47946614	47949308
ENSE00003901652	47941571	47941813

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 95.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.7712 / max 170.6950, expressed in 1775 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161389	14.4559	1759
161390	9.8516	1691
161391	0.4637	205

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.32	gold quality
liver	UBERON:0002107	94.91	gold quality
kidney epithelium	UBERON:0004819	94.59	gold quality
adult mammalian kidney	UBERON:0000082	91.20	gold quality
tibialis anterior	UBERON:0001385	89.60	silver quality
ileal mucosa	UBERON:0000331	88.74	gold quality
islet of Langerhans	UBERON:0000006	88.57	gold quality
right adrenal gland cortex	UBERON:0035827	87.90	gold quality
right adrenal gland	UBERON:0001233	87.69	gold quality
colonic epithelium	UBERON:0000397	87.67	gold quality
kidney	UBERON:0002113	87.44	gold quality
hypothalamus	UBERON:0001898	87.32	gold quality
mucosa of transverse colon	UBERON:0004991	86.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.84	gold quality
muscle of leg	UBERON:0001383	86.67	gold quality
left adrenal gland	UBERON:0001234	86.56	gold quality
prefrontal cortex	UBERON:0000451	86.54	gold quality
gastrocnemius	UBERON:0001388	86.54	gold quality
left adrenal gland cortex	UBERON:0035825	86.44	gold quality
anterior cingulate cortex	UBERON:0009835	86.32	gold quality
adrenal gland	UBERON:0002369	85.82	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.78	gold quality
rectum	UBERON:0001052	85.75	gold quality
caudate nucleus	UBERON:0001873	85.62	gold quality
cortex of kidney	UBERON:0001225	85.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.40	gold quality
right frontal lobe	UBERON:0002810	85.39	gold quality
adrenal cortex	UBERON:0001235	85.31	gold quality
substantia nigra	UBERON:0002038	85.24	gold quality
skeletal muscle organ	UBERON:0014892	85.20	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting PNPO, 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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-609	99.82	64.26	505
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107

Literature-anchored findings (GeneRIF, showing 17)

• Results describe a combined computer and biochemical approach to characterize human pyridoxine 5’-phosphate oxidase (PNPO). (PMID:15182361)
• several mutations appear to cause epilepsy (PMID:15772097)
• We examined 8 single nucleotide polymorphisms (SNPs) in PNPO and its 5’-flanking regions in 359 schizophrenia patients and 582 control subjects. (PMID:17851041)
• Sequencing of the PNPO gene revealed a novel homozygous nonsense mutationt in exon 3 in the neonatal and infantile seizure. (PMID:18485777)
• PNP oxidase R229W mutation identified in patients with neonatal epileptic encephalopathy sgnificantly affect the catalytic efficiency of the enzyme. (PMID:19759001)
• provide evidence that a single arginine residue of the C terminus of pyridoxal 5’-phosphate synthase is responsible for coordinating co-operativity in this elaborate protein machinery (PMID:21283685)
• Generalized epilepsies implicates susceptibility genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. (PMID:22949513)
• One sequence variant, R116Q, a single nucleotide polymorphism that has been reported in the general population, was found to have an effect on PNPO activity. (PMID:24645144)
• Challenge to the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5’-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. (PMID:24658933)
• Exome sequencing revealed that the patient was compound heterozygous for pathogenic mutations [c.546+1G>A (IVS5+1 G>A) and c.620delG (p.G207VfsX215)] in the PNPO gene. (PMID:26535729)
• data support a pathogenic role of the c.347G>A (p.Arg116Gln) mutation in PNPO deficiency; the later onset of symptoms and the milder epilepsy phenotype of these expand the disease phenotype (PMID:28818555)
• TGF-beta1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p in epithelial ovarian cancer. (PMID:29238081)
• results reveal the biological function and a regulatory mechanism of PNPO, in which the MALAT1/miR-216b-5p/PNPO axis may be important in breast invasive ductal carcinoma development (PMID:30982780)
• Molecular characterization of pyridoxine 5’-phosphate oxidase and its pathogenic forms associated with neonatal epileptic encephalopathy. (PMID:32788630)
• Phenotypic and molecular spectrum of pyridoxamine-5’-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5’-phosphate oxidase deficiency. (PMID:32888189)
• Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5’-Phosphate Oxidase-Dependent Epilepsy. (PMID:34769443)
• Activation of human RNA lariat debranching enzyme Dbr1 by binding protein TTDN1 occurs though an intrinsically disordered C-terminal domain. (PMID:37507019)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnpo	ENSDARG00000017612
mus_musculus	Pnpo	ENSMUSG00000018659
rattus_norvegicus	Pnpo	ENSRNOG00000046493
drosophila_melanogaster	sgll	FBGN0051472
caenorhabditis_elegans		WBGENE00018996

Protein

Protein identifiers

Pyridoxine-5’-phosphate oxidase — Q9NVS9 (reviewed: Q9NVS9)

Alternative names: Pyridoxamine-phosphate oxidase

All UniProt accessions (8): Q9NVS9, A0A286YF16, A0A286YF38, A0A286YFA1, A0A286YFL3, J3QQV6, J3QQZ9, V9HW45

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidation of either pyridoxine 5’-phosphate (PNP) or pyridoxamine 5’-phosphate (PMP) into pyridoxal 5’-phosphate (PLP).

Subunit / interactions. Homodimer.

Tissue specificity. Ubiquitous. Expressed in liver, brain, lung, prostate and stomach (at protein level).

Disease relevance. Pyridoxine-5’-phosphate oxidase deficiency (PNPOD) [MIM:610090] The main feature of neonatal epileptic encephalopathy is the onset within hours of birth of a severe seizure disorder that does not respond to anticonvulsant drugs and can be fatal. Seizures can cease with the administration of PLP, being resistant to treatment with pyridoxine,. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FMN per subunit.

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

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the pyridoxamine 5’-phosphate oxidase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NVS9-1	1	yes
Q9NVS9-2	2
Q9NVS9-3	3
Q9NVS9-4	4

RefSeq proteins (1): NP_060599* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000659	Pyridox_Oxase	Family
IPR011576	Pyridox_Oxase_N	Domain
IPR012349	Split_barrel_FMN-bd	Homologous_superfamily
IPR019576	Pyridoxamine_oxidase_dimer_C	Domain
IPR019740	Pyridox_Oxase_CS	Conserved_site

Pfam: PF01243, PF10590

Enzyme classification (BRENDA):

• EC 1.4.3.5 — pyridoxal 5’-phosphate synthase (BRENDA: 51 organisms, 88 substrates, 62 inhibitors, 131 Km, 57 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PYRIDOXINE 5’-PHOSPHATE	0.0003–2.4	60
PYRIDOXAMINE 5’-PHOSPHATE	0.0013–1	28
O2	0.085–0.182	3
5’-METHYLPYRIDOXINE-PHOSPHATE	0.0059–0.031	2
FMN	—	2
5’-HOMOPYRIDOXINE-PHOSPHATE	0.0059	1
5’-PHOSPHO-PYRIDOXAL-O-CARBOXYMETHYLOXIME	0.025	1
5’-PHOSPHO-PYRIDOXALOXIME	0.021	1
5’-PHOSPHO-PYRIDOXYL-3-AMINOBENZOATE	0.01	1
5’-PHOSPHO-PYRIDOXYL-3-L-ALANINE	0.035	1
5’-PHOSPHO-PYRIDOXYL-4-AMINOBENZOATE	0.01	1
5’-PHOSPHO-PYRIDOXYL-4-AMINOBUTYRATE	0.03	1
5’-PHOSPHO-PYRIDOXYL-5-AMINOVALERATE	0.03	1
5’-PHOSPHO-PYRIDOXYL-ANILINE	0.01	1
ALPHA-N-(5’-PHOSPHO-4’-PYRIDOXYL)-L-LYSINE	0.2	1

Catalyzed reactions (Rhea), 2 shown:

• pyridoxine 5’-phosphate + O2 = pyridoxal 5’-phosphate + H2O2 (RHEA:15149)
• pyridoxamine 5’-phosphate + O2 + H2O = pyridoxal 5’-phosphate + H2O2 + NH4(+) (RHEA:15817)

UniProt features (46 total): binding site 13, strand 11, helix 6, sequence variant 5, splice variant 4, mutagenesis site 3, modified residue 2, chain 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8ROS	X-RAY DIFFRACTION	1.55
6H00	X-RAY DIFFRACTION	1.66
8QYT	X-RAY DIFFRACTION	1.69
1NRG	X-RAY DIFFRACTION	1.95
3HY8	X-RAY DIFFRACTION	2.5
8QYW	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVS9-F1	89.04	0.79

Functional residue map

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

Ligand- & substrate-binding residues (13): 42–45; 174–175; 219; 225–227; 229; 95–98; 100; 110–111; 116–117; 139; 157; 161 …

Post-translational modifications (2): 238, 241

Mutagenesis-validated functional residues (3):

Position	Phenotype
1–72	loss of catalytic activity.
1–56	has no effect on the catalytic activity.
238–261	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 252 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, KOYAMA_SEMA3B_TARGETS_UP, GOBP_VITAMIN_BIOSYNTHETIC_PROCESS, GOBP_ALDEHYDE_METABOLIC_PROCESS, HAN_SATB1_TARGETS_DN, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, GOBP_VITAMIN_METABOLIC_PROCESS, GRADE_COLON_AND_RECTAL_CANCER_UP, CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION_DN, GOMF_FMN_BINDING, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (4): pyridoxine biosynthetic process (GO:0008615), pyridoxamine metabolic process (GO:0042818), pyridoxal 5’-phosphate biosynthetic process (GO:0042823), pyridoxal 5’-phosphate metabolic process (GO:0042822)

GO Molecular Function (7): pyridoxamine phosphate oxidase activity (GO:0004733), FMN binding (GO:0010181), pyridoxal phosphate binding (GO:0030170), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-NH2 group of donors (GO:0016638)

GO Cellular Component (2): mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vitamin B6 biosynthetic process	2
vitamin B6 metabolic process	2
anion binding	2
cytoplasm	2
pyridoxine metabolic process	1
pyridoxal 5’-phosphate metabolic process	1
aldehyde biosynthetic process	1
organophosphate biosynthetic process	1
aldehyde metabolic process	1
organophosphate metabolic process	1
oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor	1
pyridoxal 5’-phosphate biosynthetic process	1
ribonucleotide binding	1
vitamin B6 binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
oxidoreductase activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1607 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPO	DDC	P20711	896
PNPO	PDXK	O00764	845
PNPO	PLPBP	O94903	811
PNPO	ALDH7A1	P49419	682
PNPO	PDXP	Q96GD0	647
PNPO	SLC25A22	Q9H936	588
PNPO	CDKL5	O76039	551
PNPO	PRR15L	Q9BU68	545
PNPO	NAXD	Q8IW45	541
PNPO	SCN1A	P35498	528
PNPO	STXBP1	P61764	525
PNPO	PCDH19	Q8TAB3	514
PNPO	KCNQ2	O43526	512
PNPO	NHLRC3	Q5JS37	507
PNPO	SCN1B	Q07699	497

IntAct

44 interactions, top by confidence:

A	B	Type	Score
PNPO	AGTRAP	psi-mi:“MI:0915”(physical association)	0.720
AGTRAP	PNPO	psi-mi:“MI:0915”(physical association)	0.720
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
MTERF1	PNPO	psi-mi:“MI:0915”(physical association)	0.590
PNPO	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
LIME1	PNPO	psi-mi:“MI:0915”(physical association)	0.560
ARL6IP6	YKT6	psi-mi:“MI:0914”(association)	0.530
MOK	H1-3	psi-mi:“MI:0914”(association)	0.530
MYO1C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Junb	RGPD3	psi-mi:“MI:0914”(association)	0.350
SLC25A32	NEDD8-MDP1	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
FBXO25	ARHGAP1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
SPANXN4	UBA6	psi-mi:“MI:0914”(association)	0.350
C19orf25	NBAS	psi-mi:“MI:0914”(association)	0.350
FGB	KIF2A	psi-mi:“MI:0914”(association)	0.350
HOXC5	PDLIM1	psi-mi:“MI:0914”(association)	0.350
CARTPT	MEIS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): PNPO (Affinity Capture-MS), PNPO (Affinity Capture-MS), PNPO (Affinity Capture-MS), PNPO (Affinity Capture-MS), ECE2 (Co-fractionation), FH (Co-fractionation), GMPPB (Co-fractionation), HSPE1 (Co-fractionation), PNPO (Co-fractionation), PNPO (Co-fractionation), PNPO (Co-fractionation), PRCP (Co-fractionation), RABIF (Co-fractionation), SUGT1 (Co-fractionation), TALDO1 (Co-fractionation)

ESM2 similar proteins: A0A0P0WL81, A0A1D6L709, C0HLA0, O19015, O24325, O35448, O70489, O75629, O88668, P16278, P52708, Q01458, Q0DCM5, Q0DZ85, Q0INM3, Q0IZZ8, Q0J6H8, Q0P6H9, Q10MX4, Q1JQA0, Q2UXF7, Q5E9K3, Q5M872, Q5N8X6, Q5VQG4, Q5XI31, Q5Z678, Q5ZJ73, Q60HF6, Q67WE2, Q6NQ51, Q6PD26, Q6YX89, Q6Z7I3, Q6ZIF9, Q7X6J9, Q7XUR3, Q852M4, Q8BWN8, Q8BXJ9

Diamond homologs: A0M2G0, A1ABI3, A1TWZ3, A1W7K9, A3M9W4, A4JHA1, A4SWL7, A4VJR0, A5FB76, A5VZL6, A6H098, A6V9E9, A7ZMA0, A8A0I1, A8EV17, B0C079, B0JI39, B0KUA9, B0SGE9, B0SPV0, B0V9C9, B0VNC8, B1IQB6, B1J1C4, B1LEP8, B1WR90, B1XFV0, B2I1H7, B2IX27, B2SY78, B2U2D8, B2VEN4, B3R5Q8, B5Z472, B6IB77, B7ICC6, B7JZR4, B7K9I2, B7L5J1, B7LQN2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	12
Uncertain significance	158
Likely benign	153
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323480	NM_018129.4(PNPO):c.178A>T (p.Lys60Ter)	Pathogenic
1412292	NM_018129.4(PNPO):c.263+1G>C	Pathogenic
1452659	NM_018129.4(PNPO):c.346C>T (p.Arg116Ter)	Pathogenic
1704283	NM_018129.4(PNPO):c.546+1G>A	Pathogenic
1704285	NM_018129.3(PNPO):c.620delG	Pathogenic
206451	NM_018129.4(PNPO):c.674G>T (p.Arg225Leu)	Pathogenic
206458	NM_018129.4(PNPO):c.98A>T (p.Asp33Val)	Pathogenic
206460	NM_018129.4(PNPO):c.448_451del (p.Pro150fs)	Pathogenic
2128382	NM_018129.4(PNPO):c.422_433del (p.Arg141_Gly144del)	Pathogenic
223153	NM_018129.4(PNPO):c.674G>A (p.Arg225His)	Pathogenic
2426449	NC_000017.10:g.(?46019042)(46024148_?)del	Pathogenic
2736611	NM_018129.4(PNPO):c.246del (p.Leu83fs)	Pathogenic
2882403	NM_018129.4(PNPO):c.69dup (p.His24fs)	Pathogenic
3613711	NM_018129.4(PNPO):c.123C>A (p.Tyr41Ter)	Pathogenic
3702113	NM_018129.4(PNPO):c.364-1G>C	Pathogenic
4769621	NM_018129.4(PNPO):c.118_119del (p.Ser40fs)	Pathogenic
6524	NM_018129.4(PNPO):c.364-1G>A	Pathogenic
6525	NM_018129.4(PNPO):c.784T>C (p.Ter262Gln)	Pathogenic
6526	NM_018129.4(PNPO):c.520C>T (p.Gln174Ter)	Pathogenic
849386	NM_018129.4(PNPO):c.284G>A (p.Arg95His)	Pathogenic
967984	NM_018129.4(PNPO):c.205delinsTTTCCCCT (p.Ala69fs)	Pathogenic
1467523	NM_018129.4(PNPO):c.547-2A>T	Likely pathogenic
1696642	NM_018129.4(PNPO):c.418-1G>C	Likely pathogenic
1810261	NM_018129.4(PNPO):c.363+5G>A	Likely pathogenic
2503803	NM_018129.4(PNPO):c.563dup (p.Asn188fs)	Likely pathogenic
2736612	NM_018129.4(PNPO):c.352G>A (p.Gly118Arg)	Likely pathogenic
2798104	NM_018129.4(PNPO):c.547-1G>A	Likely pathogenic
2822323	NM_018129.4(PNPO):c.138+1G>A	Likely pathogenic
3582203	NM_018129.4(PNPO):c.60del (p.Tyr21fs)	Likely pathogenic
3582204	NM_018129.4(PNPO):c.434del (p.Pro145fs)	Likely pathogenic

SpliceAI

1115 predictions. Top by Δscore:

Variant	Effect	Δscore
17:47944607:T:A	acceptor_gain	1.0000
17:47944611:CCTA:C	acceptor_loss	1.0000
17:47944614:A:AG	acceptor_gain	1.0000
17:47944614:A:G	acceptor_loss	1.0000
17:47944615:G:GA	acceptor_gain	1.0000
17:47944615:GA:G	acceptor_gain	1.0000
17:47944615:GAGA:G	acceptor_gain	1.0000
17:47944615:GAGAT:G	acceptor_gain	1.0000
17:47944705:G:GT	donor_gain	1.0000
17:47944706:A:T	donor_gain	1.0000
17:47944712:GCTG:G	donor_gain	1.0000
17:47944714:TGG:T	donor_loss	1.0000
17:47944716:G:GG	donor_gain	1.0000
17:47944716:G:T	donor_loss	1.0000
17:47944717:T:A	donor_loss	1.0000
17:47945855:GAGCA:G	acceptor_loss	1.0000
17:47945856:AGCAG:A	acceptor_loss	1.0000
17:47945857:GCA:G	acceptor_loss	1.0000
17:47945858:CA:C	acceptor_loss	1.0000
17:47945859:A:T	acceptor_loss	1.0000
17:47945860:GGTGC:G	acceptor_gain	1.0000
17:47946304:A:AG	acceptor_gain	1.0000
17:47946305:A:G	acceptor_gain	1.0000
17:47946321:A:AG	acceptor_gain	1.0000
17:47946322:G:GA	acceptor_gain	1.0000
17:47946612:AGG:A	acceptor_gain	1.0000
17:47946613:GGG:G	acceptor_gain	1.0000
17:47946750:G:GT	donor_gain	1.0000
17:47941811:G:GT	donor_gain	0.9900
17:47941888:G:T	donor_gain	0.9900

AlphaMissense

1707 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:47945608:G:C	R138P	0.998
17:47945915:T:C	F158L	0.998
17:47945917:C:A	F158L	0.998
17:47945917:C:G	F158L	0.998
17:47944702:A:T	K117I	0.997
17:47944703:A:C	K117N	0.997
17:47944703:A:T	K117N	0.997
17:47946649:T:C	F218S	0.997
17:47945575:C:A	A127D	0.996
17:47945592:T:A	W133R	0.996
17:47945592:T:C	W133R	0.996
17:47946651:T:A	W219R	0.996
17:47946651:T:C	W219R	0.996
17:47944652:G:C	K100N	0.995
17:47944652:G:T	K100N	0.995
17:47945594:G:C	W133C	0.995
17:47945594:G:T	W133C	0.995
17:47945873:G:C	G144R	0.995
17:47945957:A:C	S172R	0.995
17:47945959:C:A	S172R	0.995
17:47945959:C:G	S172R	0.995
17:47945966:A:C	S175R	0.995
17:47945968:T:A	S175R	0.995
17:47945968:T:G	S175R	0.995
17:47946648:T:C	F218L	0.995
17:47946650:C:A	F218L	0.995
17:47946650:C:G	F218L	0.995
17:47944695:A:C	S115R	0.994
17:47944697:T:A	S115R	0.994
17:47944697:T:G	S115R	0.994

dbSNP variants (sampled 300 via entrez): RS1000094020 (17:47947825 C>A,T), RS1000408776 (17:47945632 A>G), RS1000423388 (17:47947365 C>G), RS1001170957 (17:47945122 C>T), RS1001766161 (17:47945483 C>G), RS1001943799 (17:47940932 C>G), RS1001953658 (17:47941314 G>C), RS1002103272 (17:47947117 T>G), RS1002338292 (17:47949116 C>T), RS1002510967 (17:47945199 G>A), RS1003891321 (17:47948349 T>A,C), RS1003922382 (17:47948773 T>A), RS1003945294 (17:47939718 C>G), RS1004067619 (17:47940887 T>G), RS1004565081 (17:47941129 C>G)

Disease associations

OMIM: gene MIM:603287 | disease phenotypes: MIM:610090, MIM:600794

GenCC curated gene-disease

Disease	Classification	Inheritance
pyridoxal phosphate-responsive seizures	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pyridoxal phosphate-responsive seizures	Definitive	AR

Mondo (3): pyridoxal phosphate-responsive seizures (MONDO:0012407), fetal growth restriction (MONDO:0005030), neuronopathy, distal hereditary motor, type 5A (MONDO:0015353)

Orphanet (2): Pyridoxamine-5-phosphate deficiency-developmental and epileptic encephalopathy (Orphanet:79096), Distal hereditary motor neuropathy type 5 (Orphanet:139536)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000496	Abnormality of eye movement
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001336	Myoclonus
HP:0001508	Failure to thrive
HP:0001560	Abnormality of the amniotic fluid
HP:0001583	Rotary nystagmus
HP:0001622	Premature birth
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002283	Global brain atrophy
HP:0002317	Unsteady gait
HP:0003785	Decreased CSF homovanillic acid concentration
HP:0005522	Pyridoxine-responsive sideroblastic anemia
HP:0005961	Hypoargininemia
HP:0008872	Feeding difficulties in infancy
HP:0008936	Axial hypotonia
HP:0010851	EEG with burst suppression
HP:0010895	Abnormal circulating glycine concentration
HP:0010900	Abnormal circulating threonine concentration
HP:0010904	Abnormal circulating histidine concentration
HP:0010909	Abnormal circulating arginine concentration

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001662_4	Generalized epilepsy	9.000000e-09
GCST005951_17	Body mass index	3.000000e-09
GCST007353_10	Generalized epilepsy	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450
C566449	Pyridoxamine 5-Prime-Phosphate Oxidase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3271932 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.26	Ki	550	nM	CHEMBL3275147

PubChem BioAssay actives

1 with measured affinity, of 2 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-ethynyl-5-hydroxy-6-methyl-3-pyridinyl)methyl dihydrogen phosphate	1147926: Non-competitive inhibition of pyridoxine phosphate oxidase (unknown origin) assessed as oxidation of pyridoxol 5’-phosphate by Lineweaver-Burk plot analysis	ki	0.5500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
sodium arsenite	increases expression, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
7,3’-dihydroxy-4’-methoxyisoflavone	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3282830	Binding	Non-competitive inhibition of pyridoxine phosphate oxidase (unknown origin) assessed as oxidation of pyridoxol 5’-phosphate by Lineweaver-Burk plot analysis	4-Halovinyl- and 4-ethynyl-4-deformylpyridoxal derivatives and related analogues as potentially irreversible antagonists of vitamin B6. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9NW	Ubigene HEK293 PNPO KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00347867	PHASE4	UNKNOWN	Viagra for the Treatment of IUGR
NCT00909974	PHASE4	COMPLETED	Effect of Prenatal Nutritional Supplementation on Birth Outcome in Hounde District, Burkina Faso
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01390051	PHASE4	COMPLETED	Can Low Molecular Weight Heparin During Pregnancy With Intrauterine Growth Restriction Increase Birth Weight?
NCT01695070	PHASE4	COMPLETED	Melatonin to Prevent Brain Injury in Unborn Growth Restricted Babies
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT05029778	PHASE4	UNKNOWN	Arginine + Citrulline as a Supplement for Weight Gain in Fetus With a Decrease in Their Growth Curve
NCT05800938	PHASE4	COMPLETED	The Effect of Oral Isosorbide Mononitrate Therapy on Umbilical Artery Doppler Resistance Index in Pregnancies With Intrauterine Growth Restriction: Prospective Randomized Control Trial
NCT07171086	PHASE4	NOT_YET_RECRUITING	AI-POCUS for Maternal and Neonatal Health in Ethiopia
NCT00174252	PHASE3	COMPLETED	Study Aimed At Improving Height With Genotonorm In Children Born Little And/Or Light With Growth Retardation At The Age
NCT00197340	PHASE3	COMPLETED	Antepartum Chronic Epidural Therapy (ACET) to Improve Blood Flow to the Uterus, Placenta and Baby in Pre-Eclampsia and Intrauterine Growth Restriction
NCT00452491	PHASE3	COMPLETED	MAXOMAT ® in the Treatment of Severe Early Onset Intrauterine Growth Retardation on Pre-pubertal Children
NCT01073605	PHASE3	COMPLETED	Genotropin Treatment in Short Prepubertal Children With Intra-Uterine Growth Retardation
NCT02336243	PHASE3	UNKNOWN	A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders
NCT02590536	PHASE3	COMPLETED	A Trial Evaluating the Role of Sildenafil in the Treatment of Fetal Growth Restriction
NCT02672566	PHASE3	COMPLETED	Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction
NCT03177824	PHASE3	UNKNOWN	Sildenafil Citrate for Treatment of Growth-restricted Fetuses
NCT03230162	PHASE3	UNKNOWN	Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment
NCT03324139	PHASE3	COMPLETED	Treatment of Intrauterine Growth Restriction With Low Molecular Heparin.
NCT03669185	PHASE3	UNKNOWN	Pentaerithrityl Tetranitrate (PETN) for Secondary Prevention of Intrauterine Growth Restriction
NCT04084990	PHASE3	TERMINATED	Sleep Apnea and Fetal Growth Restriction
NCT04356326	PHASE3	RECRUITING	Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy
NCT04557475	PHASE3	WITHDRAWN	Transplacental Aspirin Therapy for Early Onset Fetal Growth Restriction
NCT04762992	PHASE3	ENROLLING_BY_INVITATION	LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)
NCT05253781	PHASE3	COMPLETED	Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE)
NCT05651347	PHASE3	RECRUITING	Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction
NCT05774236	PHASE3	COMPLETED	Cook´s Balloon Versus Dinoprostone for Labor Induction of Term Pregnancies With Fetal Growth Restriction
NCT06497959	PHASE3	RECRUITING	Study of Placental Vascularization Using Contrast Ultrasound
NCT02280031	PHASE2	COMPLETED	Effect of Low Dose Aspirin on Birthweight in Twins: The GAP Trial.
NCT02425436	PHASE2	COMPLETED	Role of Ginkgo Biloba Extract in IUGR
NCT02678221	PHASE2	UNKNOWN	Sildenafil Citrate for the Management of Asymmetrical Intrauterine Growth Restriction
NCT02696577	PHASE2	COMPLETED	The Effect of Omega 3 on Pregnancy Complicated by Asymmetrical Intrauterine Growth Restriction
NCT07098975	PHASE2	RECRUITING	Statin Intervention for Severe Early-Onset Placental Insufficiency. (STATIN-PRE Trial)
NCT04508751	PHASE1	COMPLETED	PED NEONAT 20-000599 Fetal Body Composition
NCT06565728	PHASE1	COMPLETED	Vitamin D Versus Sildenafil Citrate in Fetal Growth Restriction
NCT07549295	PHASE1	ENROLLING_BY_INVITATION	Melatonin and Perinatal Outcomes in MVM-Related Fetal Growth Restriction (MIMVMFGR)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT01107782	PHASE2/PHASE3	UNKNOWN	Sildenafil and Uteroplacental Perfusion