NAXE

Chr 1AR

NAD(P)HX epimerase

Also known as: AIBP, APOA1BP, PEBEL, YJEFN1

NCBI Gene: 128240 ENSG00000163382 UniProt: Q8NCW5 OMIM: 608862

The NAXE protein catalyzes the epimerization of damaged forms of NAD(P)H and accelerates cholesterol efflux from endothelial cells to high-density lipoprotein. Biallelic mutations cause autosomal recessive progressive encephalopathy with early onset, characterized by brain edema and leukoencephalopathy. The gene shows low constraint to loss-of-function variation (pLI <0.001), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.311 OMIM phenotype

Clinical Summary— NAXE

🧬

Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 65 VUS of 166 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.75

OE 0.78 (0.48–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.61Z-score

OE missense 0.87 (0.76–1.00)

150 obs / 172.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.48–1.31)

0≤0.351.4

Missense OE?0.87 (0.76–1.00)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 10 / 12.9Missense obs/exp: 150 / 172.4Syn Z: 0.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNAXE-related lethal neurometabolic disorder of early childhoodLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7035th %ile

GOF

0.5661th %ile

LOF

0.3355th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic7

VUS65

Likely Benign42

Benign24

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	4	2	0	18
Likely Pathogenic	6	1	0	0	7
VUS	3	56	3	3	65
Likely Benign	0	1	14	27	42
Benign	0	2	17	5	24
Conflicting	—				3
Total	21	64	36	35	159

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap NAXE — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →