Is NEFL p.Arg23Pro (c.68G>C) pathogenic?

NEFL p.Arg23Pro (c.68G>C) is classified Uncertain significance in NEFL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-08-27). AlphaMissense: ambiguous (0.5533); Very rare (popmax 0.00034%, nfe); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Arg23Pro (c.68G>C)?

NEFL p.Arg23Pro (c.68G>C) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Arg23Pro (c.68G>C) in the general population?

NEFL p.Arg23Pro (c.68G>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about NEFL p.Arg23Pro (c.68G>C)?

AlphaMissense predicts ambiguous (score 0.5533) — an in-silico prediction, not a clinical call.

NEFL p.Arg23Pro

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.68G>C · rs745353207 · VCV1017423

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.5533	ambiguous
SaProt	LLR -5.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	24.6	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

Grpmax group 0.00034% European (non-Finnish) · 4/1,176,030 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000312% 5/1,603,916 alleles · very rare exomes 5/1,451,674 · genomes 0/152,242 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,084
European (non-Finnish)grpmax	0.00034%	294,008

Remaining individuals 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: NEFL
Protein: p.Arg23Pro
Coding: c.68G>C
MANE Select: NM_006158
dbSNP: rs745353207
Type: single nucleotide variant
Location: chr8:24956448 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 23: a modified residue (asymmetric dimethylarginine; alternate); a modified residue (omega-n-methylarginine; alternate); the 'head' region

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.Arg23Gly Uncertain significance ★★ same residue
NEFL p.Arg23Trp 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
NEFL p.Glu90Lys 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-arg23pro (accessed [today's date]).

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