Is NAXE p.Ala98= (c.294A>G) pathogenic?

NAXE p.Ala98= (c.294A>G) is classified Likely benign in NAXE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0732%, nfe).

How common is NAXE p.Ala98= (c.294A>G) in the general population?

NAXE p.Ala98= (c.294A>G) is ultra-rare (popmax 0.0732%, nfe) (gnomAD).

NAXE p.Ala98=

c.294A>G · rs145909315 · VCV2057884

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0732%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -4.1
Overall
CADD	2.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0732% European (non-Finnish) · 864/1,179,984 alleles

Filtering AF 0.0691% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0675%

Overall 0.0604% 975/1,613,946 alleles · ultra-rare exomes 927/1,461,782 · genomes 48/152,164 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
European (non-Finnish)grpmax	0.0732%	1,366
Remaining individualsnot grpmax-eligible	0.064%	1,562
African / African-American	0.0147%	6,809
South Asian	0.00549%	18,218
Admixed American	0.005%	20,000

Ashkenazi Jewish 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.Ala98=
Coding: c.294A>G
MANE Select: NM_144772
dbSNP: rs145909315
Type: single nucleotide variant
Location: chr1:156592367 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 98: 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

Similar variants

NAXE c.664+2T>A Likely pathogenic ★★ same type
NAXE p.Ser43Ter Pathogenic ★★ same type
NAXE p.Arg197Gln Uncertain significance ★★ ⚠ same type
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-ala98 (accessed [today's date]).

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