Is NEFL p.Pro440Arg (c.1319C>G) pathogenic?

NEFL p.Pro440Arg (c.1319C>G) is classified Uncertain significance in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.5843); Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Pro440Arg (c.1319C>G)?

NEFL p.Pro440Arg (c.1319C>G) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Pro440Arg (c.1319C>G) in the general population?

NEFL p.Pro440Arg (c.1319C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NEFL p.Pro440Arg (c.1319C>G)?

AlphaMissense predicts likely pathogenic (score 0.5843) — an in-silico prediction, not a clinical call.

NEFL p.Pro440Arg

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.1319C>G · VCV3637077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.5843	likely pathogenic
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	25.5	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 8.48e-05% European (non-Finnish) · 1/1,179,896 alleles

Overall 6.2e-05% 1/1,613,836 alleles · very rare exomes 0/1,461,696 · genomes 1/152,140 · 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.Pro440Arg
Coding: c.1319C>G
MANE Select: NM_006158
Type: single nucleotide variant
Location: chr8:24953646 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 440: the 'tail' region; the 'tail, subdomain a' region; 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.Pro440Leu Conflicting classifications of pathogenicity ★ same residue
NEFL p.Pro440= Likely benign ★ 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-pro440arg (accessed [today's date]).

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