NEFL

Chr 8ADAR

neurofilament light chain

Also known as: CMT1F, CMT2E, CMTDIG, NF-L, NF68, NFL, PPP1R110

NCBI Gene: 4747 ENSG00000277586 UniProt: P07196 OMIM: 162280

The protein encodes the light chain of neurofilaments, which are intermediate filament heteropolymers that comprise the axoskeleton and maintain neuronal caliber. Mutations cause Charcot-Marie-Tooth disease types 1F, 2E, and dominant intermediate G through a dominant-negative mechanism, though autosomal recessive inheritance has also been reported. These are peripheral neuropathies characterized by progressive weakness and sensory loss in the hands and feet.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/AR3 OMIM phenotypes

Clinical Summary— NEFL

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.82top 10%

GOF

0.73top 25%

LOF

0.3552th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFAbe et al. (2009) postulated that the nonsense mutation would result in loss of function, in contrast to missense mutations which result in toxic gain of function, and concluded that homozygous nonsense mutations in the NEFL gene cause a recessive disorder.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 19158810 ↗

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NEFL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Hereditary Amyloidosis, Transthyretin-RelatedAsymptomatic Carrier State

Observational Study of Neurofilament Light Chain (NfL) as a Biomarker in Asymptomatic Carriers of the Transthyretin (TTR) Variants and Patients With Hereditary Transthyretin-mediated (hATTR) Amyloidosis With Polyneuropathy

ACTIVE NOT RECRUITING

NCT06360289Alnylam PharmaceuticalsStarted 2024-04-25

Standard of Care

Mild Cognitive ImpairmentAlzheimer Disease

Cognitive Vulnerability to Stress in Individuals at Risk for Alzheimer's Disease

RECRUITING

NCT05795634Phase NAJohns Hopkins UniversityStarted 2023-03-01

Trier Social Stress Test

Muscular Atrophy, Spinal

A Study to Learn About the Safety and Effects of Salanersen (BIIB115) When Given to Babies With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Onasemnogene Abeparvovec

NOT YET RECRUITING

NCT07444450Phase PHASE3BiogenStarted 2026-09-04

SalanersenSham Procedure

Alzheimer DiseaseAlzheimer Dementia

Daily Light and Sound Stimulation to Improve Brain Functions in Alzheimer's Disease

ACTIVE NOT RECRUITING

NCT04055376Phase NAMassachusetts Institute of TechnologyStarted 2019-08-14

GENUS device (Active Settings)GENUS device (Sham Settings)

Frontotemporal Lobar Degeneration (FTLD)Progressive Supranuclear Palsy (PSP)Corticobasal Degeneration (CBD)

ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD)

RECRUITING

NCT04363684Mayo ClinicStarted 2020-03-01