How is NAD(P)HX epimerase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NAXE p.Glu268=

Q: Is NAXE p.Glu268= (c.804G>A) pathogenic?

NAXE p.Glu268= (c.804G>A) is classified Benign in NAXE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 97.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1.

Q: What condition is associated with NAXE p.Glu268= (c.804G>A)?

NAXE p.Glu268= (c.804G>A) is associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (ClinVar).

Q: How common is NAXE p.Glu268= (c.804G>A) in the general population?

NAXE p.Glu268= (c.804G>A) is common (popmax 97.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.804G>A · rs6668178 · VCV1167831

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 97.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.107	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.3, phastCons 1
Overall
CADD	7.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 97.8% East Asian · 43,907/44,872 alleles

Filtering AF 97.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 96.9%

Overall 96.3% 1,554,550/1,614,044 alleles · common exomes 1,412,099/1,461,836 · genomes 142,451/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	97.8%	1
Finnishnot grpmax-eligible	97.8%	1
Ashkenazi Jewishnot grpmax-eligible	97.6%	1
European (non-Finnish)	97.2%	1
Admixed American	97.1%	1
Remaining individualsnot grpmax-eligible	95.9%	1
Middle Eastern	93.9%	1
South Asian	92.1%	1
Amishnot grpmax-eligible	88.7%	1
African / African-American	85.4%	1

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NAXE
Protein: p.Glu268=
Coding: c.804G>A
MANE Select: NM_144772
dbSNP: rs6668178
Type: single nucleotide variant
Location: chr1:156594021 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 268: a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy and developmental delay; uncertain significance); the yjef n-terminal domain

Full NAXE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For NAD(P)HX epimerase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NAXE c.664+2T>A Likely pathogenic ★★ same condition
NAXE p.Ser43Ter Pathogenic ★★ same condition
NAXE p.Arg254Cys Uncertain significance ★★ same condition
NAXE c.291+7G>A Benign ★★ same condition
NAXE c.292-14G>A Benign ★★ same condition
NAXE c.664+28G>A Benign ★★ same condition
NAXE c.*22T>C Benign ★★ same condition
NAXE p.Ile239= Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/naxe-p-glu268 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown