Is NEFL p.Arg172= (c.516C>T) pathogenic?

NEFL p.Arg172= (c.516C>T) is classified Uncertain significance in NEFL (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 1F.

What condition is associated with NEFL p.Arg172= (c.516C>T)?

NEFL p.Arg172= (c.516C>T) is associated with Charcot-Marie-Tooth disease type 1F (ClinVar).

How common is NEFL p.Arg172= (c.516C>T) in the general population?

NEFL p.Arg172= (c.516C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Charcot-Marie-Tooth disease type 1F inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

NEFL p.Arg172=

c.516C>T · rs1803046250 · VCV909676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Charcot-Marie-Tooth disease type 1F

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 2.9	GERP 0.97, phastCons 1
Overall
CADD	17.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,180 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000312% 5/1,604,264 alleles · very rare exomes 5/1,452,000 · genomes 0/152,264 · joint denominator

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.Arg172=
Coding: c.516C>T
MANE Select: NM_006158
dbSNP: rs1803046250
Type: single nucleotide variant
Location: chr8:24956000 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.66
Residue 172: 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 1F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 1F (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

NEFL p.Arg172Cys Uncertain significance ★ ⚠ same residue
NEFL p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Asn98Ser Pathogenic/Likely pathogenic ★★ same condition
NEFL p.Glu396Lys Pathogenic ★★ same condition
NEFL p.Pro22Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
NEFL p.Tyr6Ter Pathogenic/Likely pathogenic ★★ same condition
NEFL c.-258C>G Uncertain significance ★★ same condition
NEFL p.Glu488Lys Uncertain significance ★★ ⚠ 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-arg172 (accessed [today's date]).

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