Is NEFL p.Ser130= (c.390C>G) pathogenic?

NEFL p.Ser130= (c.390C>G) is classified Likely benign in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-03). Very rare (popmax 0.00332%, sas); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Ser130= (c.390C>G)?

NEFL p.Ser130= (c.390C>G) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Ser130= (c.390C>G) in the general population?

NEFL p.Ser130= (c.390C>G) is very rare (popmax 0.00332%, sas) (gnomAD).

NEFL p.Ser130=

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.390C>G · rs1430281104 · VCV1493113

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00332%, sas)

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 -0.3	GERP -3.8, phastCons 0.032
Overall
CADD	9.688	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00332% South Asian · 3/90,344 alleles

Filtering AF 0.000882% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000445%

Overall 0.000746% 12/1,608,606 alleles · very rare exomes 11/1,456,386 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00332%	30,115
Admixed American	0.00168%	59,684
European (non-Finnish)	0.000679%	147,365

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.Ser130=
Coding: c.390C>G
MANE Select: NM_006158
dbSNP: rs1430281104
Type: single nucleotide variant
Location: chr8:24956126 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 130: the if rod domain; the 'linker 1' 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.Ser130Cys 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-ser130 (accessed [today's date]).

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