NAXD

Chr 13AR

NAD(P)HX dehydratase

Also known as: CARKD, LP3298, PEBEL2

NCBI Gene: 55739 ENSG00000213995 UniProt: Q8IW45 OMIM: 615910

NAXD encodes a mitochondrial enzyme that catalyzes ATP-dependent dehydration of NAD(P)HX to repair damaged NAD(P)H cofactors. Mutations cause autosomal recessive progressive encephalopathy with early onset, characterized by brain edema and leukoencephalopathy. The gene shows tolerance to loss-of-function variants (pLI 0.007, LOEUF 0.8), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables ATP-dependent NAD(P)H-hydrate dehydratase activity. Predicted to be involved in metabolite repair. Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.801 OMIM phenotype

Clinical Summary— NAXD

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 71 VUS of 196 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?

0.80LOEUF

pLI 0.007

Z-score 2.12

OE 0.41 (0.22–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.89Z-score

OE missense 0.84 (0.75–0.94)

203 obs / 242.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.22–0.80)

0≤0.351.4

Missense OE?0.84 (0.75–0.94)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 6 / 14.8Missense obs/exp: 203 / 242.2Syn Z: -1.21

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNAXD-related neurodegenerative disorder exacerbated by febrile illnessesLOFAR

This gene — mechanism propensity

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

0.78top 25%

GOF

0.5464th %ile

LOF

0.2775th %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

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic9

VUS71

Likely Benign72

Benign17

Conflicting6

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	6	2	1	0	9
Likely Pathogenic	7	1	1	0	9
VUS	4	61	6	0	71
Likely Benign	0	8	18	46	72
Benign	1	4	8	4	17
Conflicting	—				6
Total	18	76	34	50	184

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

View in ClinVar →

112 pathogenic / likely-pathogenic (of 127) ClinVar copy-number / structural variants overlap NAXD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →