NFASC

Chr 1AR

neurofascin

Also known as: NEDCPMD, NF, NRCAML

NCBI Gene: 23114ENSG00000163531UniProt: O94856

This gene encodes an L1 family immunoglobulin cell adhesion molecule with multiple IGcam and fibronectin domains. The protein functions in neurite outgrowth, neurite fasciculation, and organization of the axon initial segment (AIS) and nodes of Ranvier on axons during early development. Both the AIS and nodes of Ranvier contain high densities of voltage-gated Na+ (Nav) channels which are clustered by interactions with cytoskeletal and scaffolding proteins including this protein, gliomedin, ankyrin 3 (ankyrin-G), and betaIV spectrin. This protein links the AIS extracellular matrix to the intracellular cytoskeleton. This gene undergoes extensive alternative splicing, and the full-length nature of some variants has not been determined.[provided by RefSeq, May 2009]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with central and peripheral motor dysfunctionMIM #618356
AR
364
ClinVar variants
28
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NFASC
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 208 VUS of 364 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 1.000
Z-score 6.69
OE 0.12 (0.07–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.59Z-score
OE missense 0.74 (0.69–0.79)
588 obs / 793.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.07–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.69–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 8 / 67.1Missense obs/exp: 588 / 793.1Syn Z: 0.22

ClinVar Variant Classifications

364 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic6
VUS208
Likely Benign68
Benign21
Conflicting8
22
Pathogenic
6
Likely Pathogenic
208
VUS
68
Likely Benign
21
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
5
15
0
22
Likely Pathogenic
0
0
6
0
6
VUS
3
193
12
0
208
Likely Benign
0
28
11
29
68
Benign
0
3
2
16
21
Conflicting
—8
Total52294645333

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NFASC · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NEUROFASCIN; NFASC
MIM #609145 · *

Neurodevelopmental disorder with central and peripheral motor dysfunction

MIM #618356

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the genetic heterogeneity of intellectual disability.
Anazi S et al.·Hum Genet
2017
A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC.
García-González P et al.·Eur J Hum Genet
2025
Whole-exome sequencing reveals novel variants associated with abnormal uterine bleeding caused by copper intrauterine device.
Shen Y et al.·Per Med
2022
PARP3 supervises G9a-mediated repression of adhesion and hypoxia-responsive genes in glioblastoma cells.
Nguekeu-Zebaze L et al.·Sci Rep
2022
Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.
Efthymiou S et al.·Brain
2019
Case report of two children with auditory neuropathy spectrum disorder related to a neurofascin (NFASC) gene variant.
Harper JL et al.·Int J Pediatr Otorhinolaryngol
2020Case report
Neurofascin antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: from intrinsic genetic background to clinical manifestations.
Wang Z et al.·Neurol Sci
2021Review
Very high-resolution ultrasound of the distal median nerve.
Ridolfi M et al.·Clin Neurophysiol
2020
Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia.
Smigiel R et al.·Hum Mol Genet
2018Case report
Low OLFM1 and BMP6 Expression Predicts Recurrence in Early-Stage Nonsquamous NSCLC with Pure Solid Tumor Appearance.
Suda K et al.·Cancer Res Commun
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools