Is NEFL p.Gln348= (c.1044G>A) pathogenic?

NEFL p.Gln348= (c.1044G>A) is classified Uncertain significance in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). Very rare (popmax 0.00111%, sas); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Gln348= (c.1044G>A)?

NEFL p.Gln348= (c.1044G>A) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Gln348= (c.1044G>A) in the general population?

NEFL p.Gln348= (c.1044G>A) is very rare (popmax 0.00111%, sas) (gnomAD).

NEFL p.Gln348=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2E inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1044G>A · rs1234285997 · VCV655835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.32	loss · gain 0.17 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/89,948 alleles

Overall 6.27e-05% 1/1,595,560 alleles · very rare exomes 1/1,443,822 · genomes 0/151,738 · 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: NEFL
Protein: p.Gln348=
Coding: c.1044G>A
MANE Select: NM_006158
dbSNP: rs1234285997
Type: single nucleotide variant
Location: chr8:24955472 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 348: the 'coil 2b' region; the if rod domain

Full NEFL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2E (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

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NEFL p.Glu186Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu396Lys Pathogenic ★★ same condition
NEFL p.Glu90Lys Pathogenic ★★ same condition
NEFL p.Pro22Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
NEFL p.Pro8Leu Pathogenic/Likely 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/nefl-p-gln348 (accessed [today's date]).

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