Is NEFL p.Pro8Arg (c.22_23delinsAG) pathogenic?

NEFL p.Pro8Arg (c.2223delinsAG) is classified Pathogenic in NEFL (ClinVar, No assertion criteria, 3 submitters; last evaluated 2007-12-15). No gnomAD frequency available for this variant; Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Pro8Arg (c.22_23delinsAG)?

NEFL p.Pro8Arg (c.22_23delinsAG) is associated with Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease type 1F (ClinVar).

How common is NEFL p.Pro8Arg (c.22_23delinsAG) in the general population?

NEFL p.Pro8Arg (c.22_23delinsAG) is no gnomAD frequency available for this variant (gnomAD).

NEFL p.Pro8Arg

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.22_23delinsAG · rs60261494 · VCV14030

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

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.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 0.91, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic

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.Pro8Arg
Coding: c.22_23delinsAG
MANE Select: NM_006158
dbSNP: rs60261494
Type: Indel
Location: chr8:24956493 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 8: the 'head' region; a UniProt-annotated variant site (in cmt1f); a UniProt-annotated variant site (in cmt2e and cmt1f)

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

Also linked: Charcot-Marie-Tooth disease type 1F

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

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

Similar variants

NEFL p.Pro8Leu Pathogenic/Likely pathogenic ★★ same residue
NEFL p.Pro8Ser Uncertain significance ★★ ⚠ same residue
NEFL p.Pro8Ala Uncertain significance ★ ⚠ same residue
NEFL p.Pro8Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
NEFL p.Ala491Leu Uncertain significance ★★ same condition
NEFL p.Glu480Arg Uncertain significance ★★ same condition
NEFL p.Pro8Gln Pathogenic ★ same residue
NEFL p.Gln113Pro Conflicting classifications of pathogenicity ★ 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-pro8arg (accessed [today's date]).

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