Is NAXE p.Leu86Pro (c.257T>C) pathogenic?

NAXE p.Leu86Pro (c.257T>C) is classified Uncertain significance in NAXE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-08-05). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NAXE p.Leu86Pro (c.257T>C)?

NAXE p.Leu86Pro (c.257T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NAXE p.Leu86Pro (c.257T>C) in the general population?

NAXE p.Leu86Pro (c.257T>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about NAXE p.Leu86Pro (c.257T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

NAXE p.Leu86Pro

c.257T>C · rs773703382 · VCV1193587

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 3% in NAXE
REVEL	0.544	indeterminate
SaProt	LLR -16.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,276 bp · p 0.47 · regional, not allelic
Overall
CADD	33.0	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 0.00271% European (non-Finnish) · 32/1,180,052 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00204% 33/1,614,114 alleles · very rare exomes 31/1,461,880 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,877
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Leu86Pro
Coding: c.257T>C
MANE Select: NM_144772
dbSNP: rs773703382
Type: single nucleotide variant
Location: chr1:156592175 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.71
Residue 86: 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

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

Similar variants

NAXE p.Arg254Cys Uncertain significance ★★ same condition
NAXE p.Glu64Ala Uncertain significance ★★ ⚠ same condition
NAXE p.Arg197Trp Uncertain significance ★ ⚠ same condition
NAXE p.Gln234Arg Uncertain significance ★ ⚠ same condition
NAXE p.Gly124Cys Uncertain significance ★ ⚠ same condition
NAXE p.Leu8Pro Uncertain significance ★ ⚠ same condition
NAXE p.Thr281Ser Uncertain significance ★ ⚠ same condition
NAXE c.664+2T>A Likely pathogenic ★★ 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-leu86pro (accessed [today's date]).

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