Is NEFL p.Arg323Pro (c.968G>C) pathogenic?

NEFL p.Arg323Pro (c.968G>C) is classified Conflicting classifications of pathogenicity in NEFL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-17). AlphaMissense: likely pathogenic (0.9977); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Arg323Pro (c.968G>C)?

NEFL p.Arg323Pro (c.968G>C) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Arg323Pro (c.968G>C) in the general population?

NEFL p.Arg323Pro (c.968G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEFL p.Arg323Pro (c.968G>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

NEFL p.Arg323Pro

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.968G>C · rs864622499 · VCV220372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 6% in NEFL
SaProt	LLR -17.29	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.82, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEFL
Protein: p.Arg323Pro
Coding: c.968G>C
MANE Select: NM_006158
dbSNP: rs864622499
Type: single nucleotide variant
Location: chr8:24955548 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 323: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in cmt2e; uncertain significance)

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

NEFL p.Arg323Gln Uncertain significance ★ ⚠ same residue
NEFL p.Arg323= Likely benign ★ same residue
NEFL p.Arg323Trp Uncertain significance ★★ ⚠ same residue
NEFL p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Arg421Ter Pathogenic ★★ same condition
NEFL p.Asn98Ser Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu186Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu396Lys 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-arg323pro (accessed [today's date]).

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