NEFH

Chr 22

neurofilament heavy chain

Also known as: CMT2CC, NFH

NCBI Gene: 4744 ENSG00000100285 UniProt: P12036

The heavy neurofilament protein forms part of the axoskeleton that maintains neuronal caliber and may facilitate intracellular transport to axons and dendrites. Mutations cause Charcot-Marie-Tooth disease type 2CC and confer susceptibility to amyotrophic lateral sclerosis through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves dominant-negative effects disrupting normal neurofilament function.

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 functionally maintain neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the heavy neurofilament protein. This protein is commonly used as a biomarker of neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS) has been associated with mutations in this gene. [provided by RefSeq, Oct 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.06

Clinical Summary— NEFH

🧬

Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 658 VUS of 1122 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.000

Z-score 1.28

OE 0.75 (0.53–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.52Z-score

OE missense 0.93 (0.87–1.01)

470 obs / 503.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.53–1.06)

0≤0.351.4

Missense OE?0.93 (0.87–1.01)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 22 / 29.5Missense obs/exp: 470 / 503.0Syn Z: -0.52

This gene — mechanism propensity

0.7130th %ile

GOF

0.6346th %ile

LOF

0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOF1 literature citation

LOF100% of P/LP variants are LoF

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

GOFThe transfected cells appeared round and had significantly decreased axon-like projections compared to wildtype, and the aggregates trapped NEFL (162280), kinesin, and other proteins, and thus disrupted the neurofilament network in a toxic gain-of-function manner.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27040688 ↗

ClinVar Variant Classifications

1122 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic7

VUS658

Likely Benign347

Benign52

Conflicting54

Pathogenic

Likely Pathogenic

658

VUS

347

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	7	0	0	0	7
VUS	52	587	18	1	658
Likely Benign	3	35	31	278	347
Benign	1	11	23	17	52
Conflicting	—				54
Total	65	633	72	296	1,120

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap NEFH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →