Is NAXE p.Asp218Val (c.653A>T) pathogenic?

NAXE p.Asp218Val (c.653A>T) is classified Pathogenic in NAXE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-11-14). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.47e-05%, nfe); Associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy.

How common is NAXE p.Asp218Val (c.653A>T) in the general population?

NAXE p.Asp218Val (c.653A>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NAXE p.Asp218Val (c.653A>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

NAXE p.Asp218Val

Q: What condition is associated with NAXE p.Asp218Val (c.653A>T)?

NAXE p.Asp218Val (c.653A>T) is associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy (ClinVar).

c.653A>T · rs886041064 · VCV268121

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 3% in NAXE
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -16.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,276 bp · p 0.47 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 0.000124% 2/1,614,164 alleles · very rare exomes 2/1,461,882 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	8.47e-05%	1,180,038

Remaining individuals 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.Asp218Val
Coding: c.653A>T
MANE Select: NM_144772
dbSNP: rs886041064
Type: single nucleotide variant
Location: chr1:156593544 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 218: a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy and developmental delay; uncertain significance); a UniProt-annotated variant site (in pebel1); the yjef n-terminal domain; a binding site

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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NAXE c.664+2T>A Likely pathogenic ★★ same condition
NAXE p.Tyr59Ter Pathogenic ★ same condition
NAXE c.516+1G>A Pathogenic same condition
NAXE p.Ala94Asp Pathogenic same condition
NAXE p.Gln66Ter Pathogenic same condition
NAXE p.Lys270del Conflicting classifications of pathogenicity ★ same condition
NAXE p.Thr110fs Conflicting classifications of pathogenicity ★ same condition
NAXE p.Ala248fs Pathogenic 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-asp218val (accessed [today's date]).

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