Is NEFL p.Pro8Ser (c.22C>T) pathogenic?

NEFL p.Pro8Ser (c.22C>T) is classified Uncertain significance in NEFL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-03). AlphaMissense: likely benign (0.1982); No allele count reported in gnomAD v4.1 (AN 1,599,310); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Pro8Ser (c.22C>T)?

NEFL p.Pro8Ser (c.22C>T) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Pro8Ser (c.22C>T) in the general population?

NEFL p.Pro8Ser (c.22C>T) is no allele count reported in gnomAD v4.1 (AN 1,599,310) (gnomAD).

What do computational predictors say about NEFL p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.1982) — an in-silico prediction, not a clinical call.

NEFL p.Pro8Ser

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.22C>T · rs886043551 · VCV576990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1982 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,599,310)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.1982	likely benign
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,599,310). 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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_006158
dbSNP: rs886043551
Type: single nucleotide variant
Location: chr8:24956494 (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

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.Pro8Ala Uncertain significance ★ ⚠ same residue
NEFL p.Pro8Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
NEFL p.Pro8Arg Pathogenic same residue
NEFL p.Pro8Gln Pathogenic ★ same residue
NEFL p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Arg421Ter Pathogenic ★★ same condition
NEFL p.Asn98Ser 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-pro8ser (accessed [today's date]).

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