Is NEFL p.Ser27Pro (c.79T>C) pathogenic?

NEFL p.Ser27Pro (c.79T>C) is classified Uncertain significance in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-16). AlphaMissense: likely benign (0.1421); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Ser27Pro (c.79T>C)?

NEFL p.Ser27Pro (c.79T>C) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Ser27Pro (c.79T>C) in the general population?

NEFL p.Ser27Pro (c.79T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEFL p.Ser27Pro (c.79T>C)?

AlphaMissense predicts likely benign (score 0.1421) — an in-silico prediction, not a clinical call.

NEFL p.Ser27Pro

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.79T>C · rs2117255911 · VCV1469851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1421 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Charcot-Marie-Tooth disease type 2E

Computational evidence

Protein change
AlphaMissense	0.1421	likely benign
SaProt	LLR -4.46	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 3.4	GERP -0.53, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	21.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEFL
Protein: p.Ser27Pro
Coding: c.79T>C
MANE Select: NM_006158
dbSNP: rs2117255911
Type: single nucleotide variant
Location: chr8:24956437 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 27: the 'head' 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.Ser27= Uncertain significance ★ 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
NEFL p.Pro22Ser 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-ser27pro (accessed [today's date]).

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