Is NEFL p.Ser133Phe (c.398C>T) pathogenic?

NEFL p.Ser133Phe (c.398C>T) is classified Uncertain significance in NEFL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9086); Very rare (popmax 0.00837%, amr); Associated with Inborn genetic diseases.

What condition is associated with NEFL p.Ser133Phe (c.398C>T)?

NEFL p.Ser133Phe (c.398C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Ser133Phe (c.398C>T) in the general population?

NEFL p.Ser133Phe (c.398C>T) is very rare (popmax 0.00837%, amr) (gnomAD).

What do computational predictors say about NEFL p.Ser133Phe (c.398C>T)?

AlphaMissense predicts likely pathogenic (score 0.9086) — an in-silico prediction, not a clinical call.

NEFL p.Ser133Phe

c.398C>T · rs752997070 · VCV1806906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00837%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9086	likely pathogenic
SaProt	LLR -11.25	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,702 bp · p 0.058 · regional, not allelic
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00837% Admixed American · 5/59,720 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000373% 6/1,608,236 alleles · very rare exomes 6/1,455,888 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00837%	11,944
South Asian	0.00111%	90,338

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.Ser133Phe
Coding: c.398C>T
MANE Select: NM_006158
dbSNP: rs752997070
Type: single nucleotide variant
Location: chr8:24956118 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 133: the if rod domain; the 'linker 1' region

Full NEFL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2E

Similar variants

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
NEFL p.Pro8Leu 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-ser133phe (accessed [today's date]).

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