Is NAXE p.Ser43Ter (c.128C>A) pathogenic?

NAXE p.Ser43Ter (c.128C>A) is classified Pathogenic in NAXE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-16). Very rare (popmax 0.0011%, nfe); Associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1.

How common is NAXE p.Ser43Ter (c.128C>A) in the general population?

NAXE p.Ser43Ter (c.128C>A) is very rare (popmax 0.0011%, nfe) (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.Ser43Ter

Q: What condition is associated with NAXE p.Ser43Ter (c.128C>A)?

NAXE p.Ser43Ter (c.128C>A) is associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (ClinVar).

c.128C>A · rs765587923 · VCV2506103

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

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 1 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -2.4, phastCons 0.061
Overall
CADD	36.0	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 0.0011% European (non-Finnish) · 13/1,179,732 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,612,680 alleles · very rare exomes 13/1,460,498 · genomes 5/152,182 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00792%	12,627
European (non-Finnish)grpmax	0.0011%	90,748

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser43Ter
Coding: c.128C>A
MANE Select: NM_144772
dbSNP: rs765587923
Type: single nucleotide variant
Location: chr1:156591932 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 43: a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy and developmental delay; uncertain significance)

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.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.Glu268= 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-ser43ter (accessed [today's date]).

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