Is NAXE p.Arg129Ter (c.385C>T) pathogenic?

NAXE p.Arg129Ter (c.385C>T) is classified Likely pathogenic in NAXE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-13). Very rare (popmax 0.00329%, sas); Associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1.

How common is NAXE p.Arg129Ter (c.385C>T) in the general population?

NAXE p.Arg129Ter (c.385C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

How is NAD(P)HX epimerase deficiency inherited?

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

NAXE p.Arg129Ter

Q: What condition is associated with NAXE p.Arg129Ter (c.385C>T)?

NAXE p.Arg129Ter (c.385C>T) is associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (ClinVar).

c.385C>T · VCV4081529

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.04, phastCons 0.9
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,614,042 alleles · very rare exomes 3/1,461,878 · genomes 0/152,164 · joint denominator

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.Arg129Ter
Coding: c.385C>T
MANE Select: NM_144772
Type: single nucleotide variant
Location: chr1:156592458 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 129: 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 p.Arg129Gly Uncertain significance ★ ⚠ same residue
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

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-arg129ter (accessed [today's date]).

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