NAXE

Summary

NAXE (NAD(P)HX epimerase, HGNC:18453) is a protein-coding gene on chromosome 1q22, encoding NAD(P)H-hydrate epimerase (Q8NCW5). Catalyzes the epimerization of the S- and R-forms of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration.

The product of this gene interacts with apolipoprotein A-I (apoA-I), the major apolipoprotein of high-density lipoproteins (HDLs). It is secreted into some bodily fluids, and its synthesis and secretion are stimulated in vitro by incubating cells with apoA-I. The human genome contains related pseudogenes.

Source: NCBI Gene 128240 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 162 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_144772

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18453
Approved symbol	NAXE
Name	NAD(P)HX epimerase
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	AIBP, MGC119143, MGC119144, MGC119145, YJEFN1
Ensembl gene	ENSG00000163382
Ensembl biotype	protein_coding
OMIM	608862
Entrez	128240

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 27 protein_coding, 8 retained_intron, 1 nonsense_mediated_decay

ENST00000368233, ENST00000368234, ENST00000368235, ENST00000467374, ENST00000488840, ENST00000679369, ENST00000679649, ENST00000679702, ENST00000679913, ENST00000680004, ENST00000680087, ENST00000680269, ENST00000680529, ENST00000680661, ENST00000681054, ENST00000681523, ENST00000681645, ENST00000681734, ENST00000681825, ENST00000681922, ENST00000886056, ENST00000886057, ENST00000886058, ENST00000886059, ENST00000886060, ENST00000886061, ENST00000886062, ENST00000925438, ENST00000925439, ENST00000969769, ENST00000969770, ENST00000969771, ENST00000969772, ENST00000969773, ENST00000969774, ENST00000969775

RefSeq mRNA: 1 — MANE Select: NM_144772 NM_144772

CCDS: CCDS1145

Canonical transcript exons

ENST00000368235 — 6 exons

Exon	Start	End
ENSE00001073986	156592557	156592670
ENSE00001073989	156593408	156593555
ENSE00001168424	156592101	156592209
ENSE00001446657	156593882	156594299
ENSE00003478932	156592365	156592475
ENSE00003845658	156591776	156591986

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.3595 / max 480.3046, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5734	36.1641	1812
5735	0.6834	445
5736	0.2907	144
5733	0.2212	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.08	gold quality
left ventricle myocardium	UBERON:0006566	96.95	gold quality
islet of Langerhans	UBERON:0000006	96.68	gold quality
kidney epithelium	UBERON:0004819	96.67	gold quality
heart left ventricle	UBERON:0002084	96.53	gold quality
prefrontal cortex	UBERON:0000451	96.48	gold quality
mucosa of transverse colon	UBERON:0004991	96.48	gold quality
cardiac ventricle	UBERON:0002082	96.47	gold quality
right atrium auricular region	UBERON:0006631	96.45	gold quality
cardiac atrium	UBERON:0002081	96.42	gold quality
adult organism	UBERON:0007023	96.33	gold quality
myocardium	UBERON:0002349	96.10	gold quality
corpus epididymis	UBERON:0004359	96.05	gold quality
heart	UBERON:0000948	96.04	gold quality
metanephros cortex	UBERON:0010533	96.03	gold quality
adenohypophysis	UBERON:0002196	95.97	gold quality
adult mammalian kidney	UBERON:0000082	95.92	gold quality
right adrenal gland	UBERON:0001233	95.75	gold quality
cortex of kidney	UBERON:0001225	95.67	gold quality
upper arm skin	UBERON:0004263	95.65	gold quality
left adrenal gland	UBERON:0001234	95.63	gold quality
left adrenal gland cortex	UBERON:0035825	95.62	gold quality
right adrenal gland cortex	UBERON:0035827	95.59	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.58	gold quality
substantia nigra	UBERON:0002038	95.57	gold quality
pituitary gland	UBERON:0000007	95.55	gold quality
heart right ventricle	UBERON:0002080	95.53	gold quality
ileal mucosa	UBERON:0000331	95.51	gold quality
anterior cingulate cortex	UBERON:0009835	95.46	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.05
E-CURD-112	yes	14.01
E-CURD-114	yes	11.63
E-MTAB-7303	no	1698.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting NAXE, 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-4283	100.00	66.42	2097
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-5195-5P	90.84	65.09	287

Literature-anchored findings (GeneRIF, showing 19)

• Taken together, the current study demonstrates that APN might protect against atherosclerosis by increasing HDL assembly through enhancing ABCA1 pathway and apoA-1 synthesis in the liver. (PMID:17521614)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• AIBP accelerates cholesterol efflux from endothelial cells to HDL and thereby regulates angiogenesis (PMID:23719382)
• AIBp contributes to mitotic entry and bipolar spindle assembly. (PMID:26114227)
• Study shows a homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy.This is the first report of a defect in the nicotinamide nucleotide repair system in humans. (PMID:27122014)
• NAXE Mutations Disrupt the Cellular NAD(P)HX Repair System and Cause a Lethal Neurometabolic Disorder of Early Childhood (PMID:27616477)
• These results suggest that AIBP inhibits inflammatory signaling pathways through binding to apoA-1 and stabilizing ABCA1, and subsequent alteration of lipid rafts and TLR4 in the cell membrane. (PMID:29618705)
• These results provide circumstantial evidence that the epimerase has a metabolic function beyond NAD(P)HX repair and that this function involves vitamin B6. (PMID:29654173)
• NAXE gene mutations are associated with early-onset progressive encephalopathy. (PMID:30022751)
• Study finds that AIBP was expressed in inflammatory cells in the human lung. In vitro, AIBP in the presence of surfactant reduced LPS-induced p65, ERK1/2 and p38 phosphorylation, and IL-6 secretion by alveolar macrophages. These results suggest that lung injury increases pulmonary AIBP expression, which likely serves to promote cholesterol efflux to surfactant and reduce inflammation. (PMID:30135304)
• Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment. (PMID:31745726)
• Early-onset progressive encephalopathy associated with NAXE gene variants: a case report of a Turkish child. (PMID:31758406)
• Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. (PMID:32020600)
• Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein). (PMID:32787522)
• NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1alpha signaling in hepatocellular carcinoma. (PMID:33932069)
• A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy. (PMID:34120322)
• Identification of a novel homozygous mutation in NAXE gene associated with early-onset progressive encephalopathy by whole-exome sequencing: in silico protein structure characterization, molecular docking, and dynamic simulation. (PMID:35819538)
• Nuclear Mitochondrial Disorder Due to a Variant in NAXE in Two Unrelated Indian Children. (PMID:36773198)
• Apolipoprotein A-I Binding Protein Inhibits the Formation of Infantile Hemangioma through Cholesterol-Regulated Hypoxia-Inducible Factor 1alpha Activation. (PMID:37832842)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	naxe	ENSDARG00000058806
mus_musculus	Naxe	ENSMUSG00000028070
rattus_norvegicus	Naxe	ENSRNOG00000019201
drosophila_melanogaster	Naxe	FBGN0030178
caenorhabditis_elegans	Y18D10A.3	WBGENE00012476

Paralogs (1): YJEFN3 (ENSG00000250067)

Protein

Protein identifiers

NAD(P)H-hydrate epimerase — Q8NCW5 (reviewed: Q8NCW5)

Alternative names: Apolipoprotein A-I-binding protein, NAD(P)HX epimerase, YjeF N-terminal domain-containing protein 1

All UniProt accessions (7): A0A7P0T9Y2, A0A7P0TA18, A0A7P0TAG8, A0A7P0Z426, Q5T3I3, Q5T3I4, Q8NCW5

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the epimerization of the S- and R-forms of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration. This is a prerequisite for the S-specific NAD(P)H-hydrate dehydratase to allow the repair of both epimers of NAD(P)HX. Accelerates cholesterol efflux from endothelial cells to high-density lipoprotein (HDL) and thereby regulates angiogenesis.

Subunit / interactions. Homodimer. Interacts with APOA1 and APOA2.

Subcellular location. Mitochondrion. Secreted.

Tissue specificity. Ubiquitously expressed, with highest levels in kidney, heart and liver. Present in cerebrospinal fluid and urine but not in serum from healthy patients. Present in serum of sepsis patients (at protein level).

Post-translational modifications. Undergoes physiological phosphorylation during sperm capacitation, downstream to PKA activation.

Disease relevance. Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 1 (PEBEL1) [MIM:617186] An autosomal recessive severe neurometabolic disorder characterized by severe leukoencephalopathy usually associated with a trivial febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures. Disease course is rapidly progressive, leading to coma, global brain atrophy, and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 potassium ion per subunit.

Similarity. Belongs to the NnrE/AIBP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NCW5-1	1	yes
Q8NCW5-2	2

RefSeq proteins (1): NP_658985* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004443	YjeF_N_dom	Domain
IPR032976	YJEFN_prot_NAXE-like	Family
IPR036652	YjeF_N_dom_sf	Homologous_superfamily

Pfam: PF03853

Enzyme classification (BRENDA):

• EC 5.1.99.6 — NAD(P)H-hydrate epimerase (BRENDA: 7 organisms, 9 substrates, 0 inhibitors, 4 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(6S)-6BETA-HYDROXY-1,4,5,6-TETRAHYDRONICOTINAMID	0.0006	1
(6S)-6BETA-HYDROXY-1,4,5,6-TETRAHYDRONICOTINAMID	0.0011	1
(R)-NADH-HYDRATE	0.0016	1
(R)-NADPH-HYDRATE	0.0003	1

Catalyzed reactions (Rhea), 2 shown:

• (6R)-NADHX = (6S)-NADHX (RHEA:32215)
• (6R)-NADPHX = (6S)-NADPHX (RHEA:32227)

UniProt features (17 total): binding site 6, sequence variant 5, modified residue 2, transit peptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NCW5-F1	86.71	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 (6): 119–123; 120; 185; 189–195; 218; 221

Post-translational modifications (2): 144, 49

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196807	Nicotinate metabolism

MSigDB gene sets: 224 (showing top): WANG_CLIM2_TARGETS_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_REGULATION_OF_CHOLESTEROL_EFFLUX, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MEMBRANE_RAFT_ORGANIZATION, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_CHOLESTEROL_EFFLUX, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_SPROUTING_ANGIOGENESIS, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, chr1q22, GOBP_REGULATION_OF_STEROL_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS

GO Biological Process (7): sprouting angiogenesis (GO:0002040), lipid transport (GO:0006869), regulation of cholesterol efflux (GO:0010874), negative regulation of angiogenesis (GO:0016525), membrane raft distribution (GO:0031580), nicotinamide nucleotide metabolic process (GO:0046496), metabolite repair (GO:0110051)

GO Molecular Function (6): nucleotide binding (GO:0000166), identical protein binding (GO:0042802), metal ion binding (GO:0046872), NAD(P)HX epimerase activity (GO:0052856), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cilium (GO:0005929), cell body (GO:0044297), extracellular exosome (GO:0070062)

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
cellular anatomical structure	3
angiogenesis	2
intracellular membrane-bounded organelle	2
cytoplasm	2
transport	1
lipid localization	1
regulation of cholesterol transport	1
cholesterol efflux	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
membrane raft organization	1
membrane raft localization	1
nucleotide metabolic process	1
pyridine-containing compound metabolic process	1
metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
protein binding	1
cation binding	1
racemase and epimerase activity	1
binding	1
catalytic activity	1
mitochondrion	1
intracellular organelle lumen	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
extracellular vesicle	1

Protein interactions and networks

STRING

1582 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAXE	APOA1	P02647	967
NAXE	NAXD	Q8IW45	864
NAXE	APOA2	P02652	768
NAXE	LRP2	P98164	715
NAXE	NUDT14	O95848	559
NAXE	MRPS23	Q9Y3D9	541
NAXE	TMEM160	Q9NX00	540
NAXE	FDX2	Q6P4F2	536
NAXE	MRPS33	Q9Y291	535
NAXE	EXOSC4	Q9NPD3	504
NAXE	CXXC1	Q9P0U4	456
NAXE	SERPINI1	Q99574	450
NAXE	PHB1	P35232	449
NAXE	PSMB6	P28072	435
NAXE	TRMT10B	Q6PF06	434

IntAct

16 interactions, top by confidence:

A	B	Type	Score
NAXE		psi-mi:“MI:0915”(physical association)	0.490
NAXE	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
H2AX	ANXA6	psi-mi:“MI:0914”(association)	0.350
MAP3K7	ACOT7	psi-mi:“MI:0914”(association)	0.350
HSPA8	AGPS	psi-mi:“MI:0914”(association)	0.350
NAXE	MANBA	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
PTP4A1	NME6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (69): APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), APOA1BP (Co-fractionation), C6orf211 (Co-fractionation), DPYD (Co-fractionation), EPS8L2 (Co-fractionation), FADD (Co-fractionation), MEMO1 (Co-fractionation), UBE2G1 (Co-fractionation), APOA1BP (Affinity Capture-MS), APOA1BP (Affinity Capture-MS)

ESM2 similar proteins: A5K3F9, A7RRZ8, A8BQZ5, A8X5H6, B0BNM1, B3L9G8, B3N0Q8, B3NW64, B4GWP5, B4IDM2, B4JJQ3, B4L8C7, B4M2R8, B4NEH6, B4PXF5, B7QDG3, B8LCD8, C3YDS7, C4YF50, D3BMU4, E0V9D8, E2QRY6, E3KGP2, E3LAQ9, E3XA68, E9HCD7, F6RCC2, F7DL67, F7FIH8, O13725, O94634, P00927, P40165, Q0PIT9, Q17GW6, Q17NP0, Q1LVI2, Q29FV5, Q4PB52, Q59VX9

Diamond homologs: A0E3W6, A1S0R2, A4H7T9, A5K3F9, A6XGL0, A7F1E9, A7RPT4, A8BQZ5, A8X5H6, A9A432, B0BNM1, B3L9G8, B3N0Q8, B3NW64, B4GWP5, B4IDM2, B4JJQ3, B4L8C7, B4M2R8, B4NEH6, B4PXF5, B5YIM0, B7QDG3, B8E2P6, B8LCD8, B9KJP6, C0NNH7, C3YDS7, C4M2B8, C4YF50, C7Z508, E0V9D8, E2QRY6, E3KGP2, E3XA68, E9HCD7, F0SLK8, F6W8I0, F7DL67, F7FIH8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	64
Likely benign	39
Benign	24

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1252042	NM_144772.3(NAXE):c.262G>T (p.Gly88Trp)	Pathogenic
1320164	NM_144772.3(NAXE):c.229del (p.Gln77fs)	Pathogenic
1333657	NM_144772.3(NAXE):c.536dup (p.Tyr180fs)	Pathogenic
2506103	NM_144772.3(NAXE):c.128C>A (p.Ser43Ter)	Pathogenic
253145	NM_144772.3(NAXE):c.281C>A (p.Ala94Asp)	Pathogenic
268116	NM_144772.3(NAXE):c.177C>A (p.Tyr59Ter)	Pathogenic
268117	NM_144772.3(NAXE):c.196C>T (p.Gln66Ter)	Pathogenic
268118	NM_144772.3(NAXE):c.516+1G>A	Pathogenic
268120	NM_144772.3(NAXE):c.743del (p.Ala248fs)	Pathogenic
268121	NM_144772.3(NAXE):c.653A>T (p.Asp218Val)	Pathogenic
2894988	NM_144772.3(NAXE):c.540T>G (p.Tyr180Ter)	Pathogenic
2956017	NM_144772.3(NAXE):c.184C>T (p.Gln62Ter)	Pathogenic
3381841	NAXE, (GGGCC)n REPEAT EXPANSION, PROMOTER	Pathogenic
3626892	NM_144772.3(NAXE):c.435del (p.Arg145fs)	Pathogenic
3681372	NM_144772.3(NAXE):c.7_23dup (p.Leu10fs)	Pathogenic
423748	NM_144772.3(NAXE):c.468_478delinsATCCCTTTCCTTGGGG (p.Gln157fs)	Pathogenic
873152	NM_144772.3(NAXE):c.565G>A (p.Gly189Ser)	Pathogenic
1320163	NM_144772.3(NAXE):c.611T>C (p.Leu204Pro)	Likely pathogenic
1324778	NM_144772.3(NAXE):c.668G>A (p.Trp223Ter)	Likely pathogenic
2637091	NM_144772.3(NAXE):c.73C>T (p.Gln25Ter)	Likely pathogenic
3767216	NM_144772.3(NAXE):c.502dup (p.Glu168fs)	Likely pathogenic
3773815	NM_144772.3(NAXE):c.664+2T>A	Likely pathogenic
4081529	NM_144772.3(NAXE):c.385C>T (p.Arg129Ter)	Likely pathogenic

SpliceAI

2016 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156591971:TGGTG:T	donor_gain	1.0000
1:156591972:GGTGA:G	donor_gain	1.0000
1:156591982:CTGAG:C	donor_loss	1.0000
1:156591983:TGAG:T	donor_loss	1.0000
1:156591984:GAGG:G	donor_loss	1.0000
1:156591985:AGGTA:A	donor_loss	1.0000
1:156591986:GGT:G	donor_loss	1.0000
1:156591987:G:GA	donor_loss	1.0000
1:156591988:T:A	donor_loss	1.0000
1:156592471:TCTTT:T	donor_gain	1.0000
1:156592473:TTT:T	donor_gain	1.0000
1:156592476:G:GG	donor_gain	1.0000
1:156592552:CCTA:C	acceptor_loss	1.0000
1:156592555:A:G	acceptor_loss	1.0000
1:156592556:G:GC	acceptor_loss	1.0000
1:156592668:GAG:G	donor_gain	1.0000
1:156592669:AGG:A	donor_loss	1.0000
1:156592671:GTA:G	donor_loss	1.0000
1:156593401:A:AG	acceptor_gain	1.0000
1:156593402:C:G	acceptor_gain	1.0000
1:156593403:CACAG:C	acceptor_loss	1.0000
1:156593404:ACAG:A	acceptor_loss	1.0000
1:156593405:C:G	acceptor_gain	1.0000
1:156593405:CAG:C	acceptor_loss	1.0000
1:156593406:A:AG	acceptor_gain	1.0000
1:156593407:G:GC	acceptor_gain	1.0000
1:156593407:GC:G	acceptor_gain	1.0000
1:156593407:GCC:G	acceptor_gain	1.0000
1:156593407:GCCC:G	acceptor_gain	1.0000
1:156593407:GCCCA:G	acceptor_gain	1.0000

AlphaMissense

1853 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156592111:G:C	A65P	1.000
1:156592123:G:C	D69H	1.000
1:156592124:A:C	D69A	1.000
1:156592124:A:T	D69V	1.000
1:156592133:T:C	L72P	1.000
1:156592150:T:C	F78L	1.000
1:156592152:C:A	F78L	1.000
1:156592152:C:G	F78L	1.000
1:156592166:T:A	L83H	1.000
1:156592166:T:C	L83P	1.000
1:156592175:T:C	L86P	1.000
1:156592180:G:A	G88R	1.000
1:156592180:G:C	G88R	1.000
1:156592180:G:T	G88W	1.000
1:156592181:G:A	G88E	1.000
1:156592181:G:T	G88V	1.000
1:156592191:T:G	C91W	1.000
1:156592418:T:G	C115W	1.000
1:156592420:G:A	G116D	1.000
1:156592426:G:A	G118E	1.000
1:156592433:T:A	N120K	1.000
1:156592433:T:G	N120K	1.000
1:156592435:G:A	G121E	1.000
1:156592440:G:C	D123H	1.000
1:156592441:A:C	D123A	1.000
1:156592441:A:T	D123V	1.000
1:156592444:G:A	G124D	1.000
1:156592454:T:G	C127W	1.000
1:156592456:C:A	A128D	1.000
1:156592459:G:C	R129P	1.000

dbSNP variants (sampled 300 via entrez): RS1000531681 (1:156591691 C>A,G,T), RS1000533369 (1:156590046 T>C), RS1000964665 (1:156591948 C>A,G), RS1001900617 (1:156590938 T>C), RS1001937972 (1:156590560 T>A,C), RS1002316846 (1:156594642 A>G), RS1003318340 (1:156593418 T>C), RS1003766785 (1:156591773 G>C), RS1004376746 (1:156592020 CGGG>C), RS1004562845 (1:156592079 T>G), RS1004812370 (1:156592307 C>G,T), RS1005234135 (1:156594799 T>C), RS1005406699 (1:156591039 T>C), RS1005791692 (1:156590831 C>G), RS1007492338 (1:156590003 G>A,C)

Disease associations

OMIM: gene MIM:608862 | disease phenotypes: MIM:617186

GenCC curated gene-disease

Disease	Classification	Inheritance
encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Limited	AR

Mondo (2): encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (MONDO:0020781), encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy (MONDO:0014960)

Orphanet (1): NAD(P)HX epimerase deficiency (Orphanet:555407)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000511	Vertical supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000711	Restlessness
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001337	Tremor
HP:0002063	Rigidity
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002181	Cerebral edema
HP:0002196	Myelopathy
HP:0002273	Tetraparesis
HP:0002283	Global brain atrophy
HP:0002318	Cervical myelopathy
HP:0002352	Leukoencephalopathy
HP:0002376	Developmental regression
HP:0002490	Increased CSF lactate
HP:0002878	Respiratory failure
HP:0003128	Lactic acidosis
HP:0003593	Infantile onset
HP:0003678	Rapidly progressive

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002079_28	Migraine - clinic-based	1.000000e-07
GCST002081_19	Migraine	1.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
microcystin RR	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
entinostat	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
nutlin 3	affects cotreatment, increases secretion	1
LDN 193189	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Arsenic	decreases expression	1
Atrazine	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Phenobarbital	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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