Is NAXE p.Cys283Phe (c.848G>T) pathogenic?

NAXE p.Cys283Phe (c.848G>T) is classified Uncertain significance in NAXE (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.882); Very rare (popmax 0.00144%, nfe).

How common is NAXE p.Cys283Phe (c.848G>T) in the general population?

NAXE p.Cys283Phe (c.848G>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about NAXE p.Cys283Phe (c.848G>T)?

AlphaMissense predicts likely pathogenic (score 0.882) — an in-silico prediction, not a clinical call.

NAXE p.Cys283Phe

c.848G>T · rs779609725 · VCV1904600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.882	likely pathogenic
REVEL	0.371	indeterminate
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,276 bp · p 0.47 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,948 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00105% 17/1,613,924 alleles · very rare exomes 13/1,461,766 · genomes 4/152,158 · 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.Cys283Phe
Coding: c.848G>T
MANE Select: NM_144772
dbSNP: rs779609725
Type: single nucleotide variant
Location: chr1:156594065 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 283: 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

Similar variants

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NAXE p.Arg254Cys Uncertain significance ★★ same type
NAXE p.Glu64Ala Uncertain significance ★★ ⚠ same type
NAXE p.Leu86Pro Uncertain significance ★★ ⚠ same type
NAXE p.Ser79Arg Uncertain significance ★★ ⚠ same type
NAXE p.Val68Leu Uncertain significance ★★ ⚠ same type

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-cys283phe (accessed [today's date]).

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