NEFH

Chr 22

neurofilament heavy chain

NCBI Gene: 4744ENSG00000100285UniProt: P12036

Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. NEFH has an important function in mature axons that is not subserved by the two smaller NF proteins. May additionally cooperate with the neuronal intermediate filament proteins PRPH and INA to form neuronal filamentous networks (By similarity)

Primary Disease Associations & Inheritance

UniProtAmyotrophic lateral sclerosis
UniProtCharcot-Marie-Tooth disease, axonal, type 2CC
599
ClinVar variants
12
Pathogenic / LP
0.00
pLI score
0
Active trials
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
12 Pathogenic / Likely Pathogenic· 329 VUS of 599 total submissions
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?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.
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?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.
0.52Z-score
OE missense 0.93 (0.87–1.01)
470 obs / 503.0 exp
Tolerant

Mild missense constraint

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.0.75 (0.53–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.87–1.01)
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.1.05
0≤1.21.6
LoF obs/exp: 22 / 29.5Missense obs/exp: 470 / 503.0Syn Z: -0.52

ClinVar Variant Classifications

599 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic4
VUS329
Likely Benign196
Benign38
Conflicting24
8
Pathogenic
4
Likely Pathogenic
329
VUS
196
Likely Benign
38
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
7
0
8
Likely Pathogenic
4
0
0
0
4
VUS
19
286
24
0
329
Likely Benign
0
21
17
158
196
Benign
0
3
23
12
38
Conflicting
—24
Total2431071170599

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

View in ClinVar →

Protein Context — Lollipop Plot

NEFH · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages.
Wang Z et al.·Cell Rep Med
2025
Unveiling the NEFH+ malignant cell subtype: Insights from single-cell RNA sequencing in prostate cancer progression and tumor microenvironment interactions.
Wang J et al.·Front Immunol
2024
Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset.
Theunissen F et al.·Sci Rep
2022
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
CHRDL1, NEFH, TAGLN and SYNM as novel diagnostic biomarkers of benign prostatic hyperplasia and prostate cancer.
Su Z et al.·Cancer Biomark
2023
Methylation of PCDH17 and NEFH as prognostic biomarker for nonmetastatic RCC: A cohort study.
Koudonas A et al.·Medicine (Baltimore)
2022Cohort
An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families.
Ando M et al.·J Hum Genet
2022
Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2.
Bian X et al.·Neurodegener Dis
2018
Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation.
Song X et al.·Eur J Neurol
2025Cohort
A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.
Yan J et al.·Neurol Sci
2021
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