Is NEFL p.Ala199= (c.597C>T) pathogenic?

NEFL p.Ala199= (c.597C>T) is classified Likely benign in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 2E.

What condition is associated with NEFL p.Ala199= (c.597C>T)?

NEFL p.Ala199= (c.597C>T) is associated with Charcot-Marie-Tooth disease type 2E (ClinVar).

How common is NEFL p.Ala199= (c.597C>T) in the general population?

NEFL p.Ala199= (c.597C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

NEFL p.Ala199=

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.597C>T · rs1423856572 · VCV1158731

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, 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 -6.4	GERP -3.8
Overall
CADD	6.391	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,700 alleles

Overall 0.000125% 2/1,604,636 alleles · very rare exomes 1/1,452,446 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,388
European (non-Finnish)grpmax	8.48e-05%	1,179,700

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala199=
Coding: c.597C>T
MANE Select: NM_006158
dbSNP: rs1423856572
Type: single nucleotide variant
Location: chr8:24955919 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 199: the if rod domain; the 'coil 1b' 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.Ala199Val 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-ala199 (accessed [today's date]).

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