Is NEFL p.Ser445fs (c.1332del) pathogenic?

NEFL p.Ser445fs (c.1332del) is classified Uncertain significance in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-03). No gnomAD frequency available for this variant; Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Ser445fs (c.1332del)?

NEFL p.Ser445fs (c.1332del) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Ser445fs (c.1332del) in the general population?

NEFL p.Ser445fs (c.1332del) is no gnomAD frequency available for this variant (gnomAD).

NEFL p.Ser445fs

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.1332del · rs2486881560 · VCV2700596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NEFL
Protein: p.Ser445fs
Coding: c.1332del
MANE Select: NM_006158
dbSNP: rs2486881560
Type: Deletion
Location: chr8:24953633 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 445: the 'tail' region; the 'tail, subdomain b (acidic)' 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.Ser445Gly Uncertain significance ★ ⚠ same residue
NEFL p.Lys481del Uncertain significance ★★ same condition
NEFL p.Ala423_Tyr424insTer Pathogenic ★ same condition
NEFL p.Glu278fs Pathogenic ★ same condition
NEFL p.Glu289fs Pathogenic ★ same condition
NEFL p.Lys267fs Pathogenic ★ same condition
NEFL p.Ala159_Gln332del Uncertain significance ★ same condition
NEFL p.Ala314_Lys315del Uncertain significance ★ 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-ser445fs (accessed [today's date]).

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