Is NEFL p.Pro22= (c.66C>T) pathogenic?

NEFL p.Pro22= (c.66C>T) is classified Conflicting classifications of pathogenicity in NEFL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-07-14). Very rare (popmax 0.000765%, nfe); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Pro22= (c.66C>T)?

NEFL p.Pro22= (c.66C>T) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Pro22= (c.66C>T) in the general population?

NEFL p.Pro22= (c.66C>T) is very rare (popmax 0.000765%, nfe) (gnomAD).

NEFL p.Pro22=

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.66C>T · rs1208531254 · VCV1806908

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000765%, nfe)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.9, phastCons 1
Overall
CADD	18.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000765% European (non-Finnish) · 9/1,176,254 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000561% 9/1,604,456 alleles · very rare exomes 9/1,452,144 · genomes 0/152,312 · 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.Pro22=
Coding: c.66C>T
MANE Select: NM_006158
dbSNP: rs1208531254
Type: single nucleotide variant
Location: chr8:24956450 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 22: the 'head' region; a UniProt-annotated variant site (in cmt2e)

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.Pro22Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
NEFL p.Pro22Ala Uncertain significance ★ ⚠ same residue
NEFL p.Pro22His Conflicting classifications of pathogenicity ★ same residue
NEFL p.Pro22Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro22 (accessed [today's date]).

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