NEFH

Summary

NEFH (neurofilament heavy chain, HGNC:7737) is a protein-coding gene on chromosome 22q12.2, encoding Neurofilament heavy polypeptide (P12036). Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.

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.

Source: NCBI Gene 4744 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease axonal type 2CC (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,125 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 77
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_021076

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7737
Approved symbol	NEFH
Name	neurofilament heavy chain
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	NF-H, NFH
Ensembl gene	ENSG00000100285
Ensembl biotype	protein_coding
OMIM	162230
Entrez	4744

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000310624

RefSeq mRNA: 1 — MANE Select: NM_021076 NM_021076

CCDS: CCDS13858

Canonical transcript exons

ENST00000310624 — 4 exons

Exon	Start	End
ENSE00000652064	29483375	29483574
ENSE00001299990	29480218	29481145
ENSE00001305244	29485723	29485847
ENSE00001326961	29488849	29491390

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6542 / max 389.9712, expressed in 323 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191607	3.6542	323

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	99.98	gold quality
pons	UBERON:0000988	99.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.77	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.58	gold quality
substantia nigra pars compacta	UBERON:0001965	99.57	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.44	gold quality
superior vestibular nucleus	UBERON:0007227	99.29	gold quality
lateral globus pallidus	UBERON:0002476	98.99	gold quality
trigeminal ganglion	UBERON:0001675	98.83	gold quality
endothelial cell	CL:0000115	98.72	gold quality
medulla oblongata	UBERON:0001896	98.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.56	gold quality
sperm	CL:0000019	98.55	gold quality
middle temporal gyrus	UBERON:0002771	98.41	gold quality
inferior olivary complex	UBERON:0002127	97.84	gold quality
primary visual cortex	UBERON:0002436	97.67	gold quality
ventral tegmental area	UBERON:0002691	96.72	gold quality
parietal lobe	UBERON:0001872	96.60	gold quality
occipital lobe	UBERON:0002021	96.52	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.43	gold quality
postcentral gyrus	UBERON:0002581	96.28	gold quality
male germ cell	CL:0000015	95.73	gold quality
cerebellar vermis	UBERON:0004720	95.55	gold quality
frontal pole	UBERON:0002795	95.16	gold quality
CA1 field of hippocampus	UBERON:0003881	95.04	gold quality
superior frontal gyrus	UBERON:0002661	94.61	gold quality
midbrain	UBERON:0001891	94.01	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.89	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.86	gold quality
substantia nigra	UBERON:0002038	93.64	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	7.20
E-MTAB-8271	no	501.68
E-CURD-53	no	292.40
E-ANND-3	no	2.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CLOCK, REST

miRNA regulators (miRDB)

56 targeting NEFH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3609	99.52	69.89	2587

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• NEFH is phosphorylated at serine 493 by GSK3b (PMID:12130654)
• NEFH gene is involved in the pathogenesis of sporadic motor neuron disease (PMID:14722583)
• mutations in neurofilaments are possible risk factors that may contribute to pathogenesis in amyotrophic lateral sclerosis in conjunction with one or more additional genetic or environmental factors, but are not significant primary causes (PMID:16084104)
• A subgroup of FTD patients had remarkably high CSF levels of NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. (PMID:17290105)
• Isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation. (PMID:17626162)
• analysis of major neurofilament subunit NF-H levels in blood and cerebrospinal fluid differentiates between patients with poor and favorable outcomes. (PMID:18319731)
• Pin1 as a possible modulator of stress-induced NF-H phosphorylation as seen in neurodegenerative disorders like AD and amyotrophic lateral sclerosis (PMID:18635547)
• Elevated pNF-H released into the serum of some affected Leber hereditary optic neuropathy patients may suggest that axonal degeneration occurs at some point after loss of visual function. (PMID:19104679)
• cerebrospinal fluid phosphorylated forms of neurofilament heavy subunit are not molecular markers of axonal damage for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) probably due to the slow progression of this disease. (PMID:19678766)
• Data show that RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo. (PMID:20140245)
• the importance of alpha-internexin and NF-L in regulating the conformations of NF-M and NF-H (PMID:20213320)
• direct evidence that NF-M/H are hyperphosphorylated in Alzheimer disease (PMID:20624930)
• Serum neurofilament protein H levels were significantly elevated in stroke patients compared to healthy controls. (PMID:21349546)
• significant in vivo information on the pathophysiology of stroke may be obtained by the determination of NfH(SMI35). (PMID:21792676)
• Data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP) is linked to progressive neuro-axonal damage (increase of NfH(SMI35)) and to progression of disease. (PMID:21858182)
• NF-H levels increase significantly faster in children who have a worse Glasgow Outcome Scale following traumatic brain injury, or died. (PMID:21976236)
• Absence of axonal neurofilaments in NFH-LacZ transgenic mice compromises axonal regeneration. (PMID:23079625)
• These data support further study of pNF-H in CSF, serum and plasma as a potential amyotrophic lateral sclerosis biomarker (PMID:23117489)
• In conclusion, pNfH represents a promising candidate for inclusion in a panel of diagnostic and prognostic biomarkers. (PMID:23134506)
• CSF and intrathecal levels and CSF/serum ratios of anti-NFH antibodies were increased in the CIS patients early developing multiple sclerosis. (PMID:23632043)
• Subconcussive repetitive trauma in amateur boxing causes a mild traumatic brain injury that may be diagnosed by CSF analysis of expressed pNFH, even without unconsciousness or concussion symptoms. (PMID:24260563)
• Data identified NEFH methylation as a candidate epigenetic marker for prognosis of RCC patients as well as prediction of anti-vascular endothelial growth factor-based therapy response. (PMID:24464810)
• pNFL-H may be useful in determining which individuals require CT imaging to assess the severity of their injury (PMID:25192482)
• Phospho-NFH levels were significantly higher in amyotrophic lateral sclerosis patients in comparison with controls, in particular in fast progressors. (PMID:25261856)
• Studied diagnostic Value of Serum Levels of GFAP, pNF-H, and NSE Compared With Clinical Findings in Severity Assessment of Human Traumatic Spinal Cord Injury. (PMID:25341992)
• This study demonstrated that Higher NF-L concentrations (beta = -0.26) were associated with functional decline in patients with vascular burden. (PMID:25633679)
• Data suggest that high CSF NfH levels are an early predictor of later brain and spinal cord atrophy in multiple sclerosis patients. (PMID:27207456)
• Findings in the dorsolateral prefrontal cortex in schizophrenia provide evidence of altered proteins involved in synaptic function (FABP4), cytoarchitecture organization (NEFH), and circadian molecular clock signaling (CSNK1E), which may be contributing to the cognitive and/or negative symptoms in this disorder. FABP4, CSNK1E and NEFH could become potentially useful biomarkers for schizophrenia. (PMID:27236410)
• Study found a significant correlation between values of 8-hydroxy-2’-deoxyguanosine and phosphorylated NF-H only in clinically isolated syndrome group. While the plasma values of 8-hydroxy-2’-deoxyguanosine reflect the degree of acute demyelination in clinically isolated syndrome, phosphorylated NF-H values reflect that in relapsing-remitting multiple sclerosis. (PMID:27295058)
• This study confirmed the general applicability of the monocentric obtained cut-off values for neurofilamens in ALS, especially for pNfH (PMID:27415180)
• Study found a significant increase of pNF-H levels in both plasma and CSF in amyotrophic lateral sclerosis patients (PMID:27423602)
• Phosphoneurofilament heavy chain level was higher in ALS patients than in controls (PMID:27538346)
• Level of neurofilament heavy chain and light chains were significantly elevated in the cerebrospinal fluid of Amyotrophic Lateral Sclerosis (ALS) patients compared to healthy controls/controls without parenchymal central nervous system involvement and ALS mimic disease patients. (PMID:27732645)
• Results provide evidence that in particular pNfH can be used as a good diagnostic biomarker of ALS at the diagnostic stage. Moreover, results indicate that NfL may be useful in monitoring disease progression in a subset of patients. (PMID:28500227)
• data support the use of Cebrospinal fluid phosphorylated NFH as a prognostic biomarker for amyotrophic lateral sclerosis. (PMID:28628244)
• Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified in two Charcot-Marie-Tooth disease families. Using electroporation of chick embryo spinal cord, confirmed that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. (PMID:28709447)
• CSF and serum pNfH concentrations are elevated in patients with ALS and correlate with the disease progression rate. Moreover, CSF pNfH correlates with the burden of motor neuron dysfunction. (PMID:29054919)
• In newborns undergoing cardiac surgery, phosphorylated axonal neurofilament heavy chain was decreased at 0 hours in both the cardiopulmonary bypass and deep hypothermic circulatory arrest groups compared to baseline. (PMID:29945509)
• the regulation of NEFM and NEFH mRNA levels by miRNAs, was investigated. (PMID:30029677)
• in newborns at risk for hypoxic ischemic encephalopathy but with normal EEGs serum level (phosphorylated) not elevated (PMID:30070096)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nefh	ENSMUSG00000020396
rattus_norvegicus	Nefh	ENSRNOG00000008716
caenorhabditis_elegans		WBGENE00018024

Protein

Protein identifiers

Neurofilament heavy polypeptide — P12036 (reviewed: P12036)

Alternative names: 200 kDa neurofilament protein, Neurofilament triplet H protein

All UniProt accessions (1): P12036

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Forms heterodimers with NEFL; which can further hetero-oligomerize (in vitro). Forms heterodimers with INA (in vitro).

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Axon.

Post-translational modifications. There are a number of repeats of the tripeptide K-S-P, NFH is phosphorylated on a number of the serines in this motif. It is thought that phosphorylation of NFH results in the formation of interfilament cross bridges that are important in the maintenance of axonal caliber. Phosphorylation seems to play a major role in the functioning of the larger neurofilament polypeptides (NF-M and NF-H), the levels of phosphorylation being altered developmentally and coincidentally with a change in the neurofilament function. Phosphorylated in the head and rod regions by the PKC kinase PKN1, leading to the inhibition of polymerization.

Disease relevance. Amyotrophic lateral sclerosis (ALS) [MIM:105400] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Disease susceptibility is associated with variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2CC (CMT2CC) [MIM:616924] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The number of repeats is shown to vary between 29 and 30.

Similarity. Belongs to the intermediate filament family.

Isoforms (2)

UniProt ID	Names	Canonical?
P12036-1	1	yes
P12036-2	2

RefSeq proteins (1): NP_066554* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010790	DUF1388	Repeat
IPR018039	IF_conserved	Conserved_site
IPR039008	IF_rod_dom	Domain

Pfam: PF00038, PF07142

UniProt features (96 total): modified residue 42, repeat 30, region of interest 12, sequence variant 5, compositionally biased region 4, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12036-F1	54.28	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (42): 76, 124, 347, 421, 511, 526, 532, 540, 546, 552, 560, 566, 574, 580, 586, 594, 600, 606, 614, 620 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 419 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOBP_RESPONSE_TO_PEPTIDE, GCANCTGNY_MYOD_Q6, GOBP_NEUROGENESIS, GOBP_ORGANELLE_TRANSPORT_ALONG_MICROTUBULE, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, BROWNE_HCMV_INFECTION_12HR_UP, CHANDRAN_METASTASIS_DN, GOBP_CELL_CELL_SIGNALING, SCHUHMACHER_MYC_TARGETS_UP, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (13): microtubule cytoskeleton organization (GO:0000226), axonogenesis (GO:0007409), cell projection assembly (GO:0030031), neurofilament bundle assembly (GO:0033693), intermediate filament bundle assembly (GO:0045110), peripheral nervous system neuron axonogenesis (GO:0048936), neurofilament cytoskeleton organization (GO:0060052), axon development (GO:0061564), postsynaptic modulation of chemical synaptic transmission (GO:0099170), regulation of organelle transport along microtubule (GO:1902513), cellular response to leukemia inhibitory factor (GO:1990830), intermediate filament cytoskeleton organization (GO:0045104), postsynaptic intermediate filament cytoskeleton organization (GO:0099185)

GO Molecular Function (8): structural constituent of cytoskeleton (GO:0005200), microtubule binding (GO:0008017), kinesin binding (GO:0019894), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), dynein complex binding (GO:0070840), structural constituent of postsynaptic intermediate filament cytoskeleton (GO:0099184), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), neurofilament (GO:0005883), postsynaptic density (GO:0014069), axon (GO:0030424), neurofibrillary tangle (GO:0097418), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic intermediate filament cytoskeleton (GO:0099160), intermediate filament (GO:0005882), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton organization	3
cellular component assembly	2
intermediate filament cytoskeleton organization	2
postsynapse	2
cellular anatomical structure	2
intermediate filament cytoskeleton	2
microtubule-based process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
cell projection organization	1
intermediate filament bundle assembly	1
intermediate filament organization	1
axonogenesis	1
peripheral nervous system neuron development	1
neuron projection development	1
modulation of chemical synaptic transmission	1
regulation of intracellular transport	1
regulation of microtubule-based movement	1
organelle transport along microtubule	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
intermediate filament-based process	1
postsynaptic cytoskeleton organization	1
structural molecule activity	1
cytoskeleton	1
tubulin binding	1
cytoskeletal protein binding	1
kinase binding	1
protein binding	1
molecular adaptor activity	1
protein-containing complex binding	1
structural constituent of cytoskeleton	1
postsynaptic intermediate filament cytoskeleton	1
postsynaptic intermediate filament cytoskeleton organization	1
structural constituent of postsynapse	1
binding	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cytoplasm	1

Protein interactions and networks

STRING

2550 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEFH	NEFL	P07196	989
NEFH	NEFM	P07197	985
NEFH	INA	Q16352	984
NEFH	CDK5	Q00535	819
NEFH	FUS	P35637	798
NEFH	SOD1	P00441	785
NEFH	TARDBP	Q13148	736
NEFH	ALS2	Q96Q42	715
NEFH	DCTN1	Q14203	704
NEFH	MBP	P02686	699
NEFH	MAPT	P10636	693
NEFH	VAPB	O95292	691
NEFH	SETX	Q7Z333	676
NEFH	FIG4	Q92562	670
NEFH	GAP43	P17677	648

IntAct

45 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
HSPD1	NEFH	psi-mi:“MI:0915”(physical association)	0.560
APP	NEFH	psi-mi:“MI:0915”(physical association)	0.560
PHAF1	PSMG1	psi-mi:“MI:0914”(association)	0.530
NEFM	VWA8	psi-mi:“MI:0914”(association)	0.530
P/V/C	KPNA3	psi-mi:“MI:0914”(association)	0.530
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
NEFH	NIFK	psi-mi:“MI:0915”(physical association)	0.400
NEFH	H1-1	psi-mi:“MI:0915”(physical association)	0.400
ERBB2	NEFH	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
TCF4	HMGB1	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
MT1M	PGP	psi-mi:“MI:0914”(association)	0.350
PI4KAP1	A2ML1	psi-mi:“MI:0914”(association)	0.350
GPATCH2L	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRSS16	KLK10	psi-mi:“MI:0914”(association)	0.350
NEFH	NEFL	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
CERS3	IGLC7	psi-mi:“MI:0914”(association)	0.350
C18orf21	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), NEFH (Affinity Capture-MS), INA (Affinity Capture-MS), NEFL (Affinity Capture-MS), NEFM (Affinity Capture-MS), TARBP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GR13, A0A571BEE2, A8MU46, E9Q9K5, F1QBY1, O01949, O02828, O43493, P05229, P06719, P08855, P09346, P10156, P12036, P12305, P12675, P20810, P20811, P27321, P29172, P35662, P35663, P38978, P51125, P54938, P57786, P70486, P82179, Q02752, Q05018, Q05019, Q09202, Q09355, Q13061, Q14093, Q27450, Q28092, Q28820, Q54IN6, Q55H65

Diamond homologs: A0A125S9M6, A0JND2, A4FUZ0, A5A6M8, A6NCN2, A7YWK3, O43790, P02542, P02545, P02547, P02548, P04104, P04260, P04261, P04262, P04263, P07196, P07744, P08551, P08928, P09010, P10999, P12035, P12036, P13647, P13648, P15241, P16884, P19013, P19246, P19527, P21619, P21910, P25691, P35908, P48671, P48672, P48678, P48679, P78385

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NEFH	up-regulates	“Neurofilament bundle assembly”
NEFH	“form complex”	“Neurofilament L/H”	binding
GSK3A	“down-regulates activity”	NEFH	phosphorylation
GSK3B	down-regulates	NEFH	phosphorylation
MAPK1	“up-regulates activity”	NEFH	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1125 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	660
Likely benign	322
Benign	52

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
2138428	NM_021076.4(NEFH):c.3008_3009del (p.Lys1003fs)	Pathogenic
225631	NM_021076.4(NEFH):c.3017_3020dup (p.Pro1008fs)	Pathogenic
870692	NM_021076.4(NEFH):c.3057dup (p.Lys1020fs)	Pathogenic
1799181	NM_021076.4(NEFH):c.3044_3045del (p.Lys1015fs)	Likely pathogenic
2575892	NM_021076.4(NEFH):c.2752del (p.Glu918fs)	Likely pathogenic
4073457	NM_021076.4(NEFH):c.646_653del (p.Leu216fs)	Likely pathogenic
804316	NM_021076.4(NEFH):c.883+1G>C	Likely pathogenic
988500	NM_021076.4(NEFH):c.3057_3060dup (p.Ter1021GluextTer?)	Likely pathogenic

SpliceAI

375 predictions. Top by Δscore:

Variant	Effect	Δscore
22:29481146:G:C	donor_loss	1.0000
22:29481147:T:G	donor_loss	1.0000
22:29483371:CCAGT:C	acceptor_loss	1.0000
22:29483372:CAG:C	acceptor_loss	1.0000
22:29483373:A:AG	acceptor_gain	1.0000
22:29483373:AGT:A	acceptor_gain	1.0000
22:29483374:G:GC	acceptor_gain	1.0000
22:29483374:GT:G	acceptor_gain	1.0000
22:29483374:GTG:G	acceptor_gain	1.0000
22:29483374:GTGA:G	acceptor_gain	1.0000
22:29483571:CCAGG:C	donor_loss	1.0000
22:29483574:GG:G	donor_loss	1.0000
22:29483575:G:C	donor_loss	1.0000
22:29483576:T:G	donor_loss	1.0000
22:29485718:CCCA:C	acceptor_loss	1.0000
22:29485719:CCAG:C	acceptor_loss	1.0000
22:29485720:CA:C	acceptor_loss	1.0000
22:29485721:A:AG	acceptor_gain	1.0000
22:29485721:A:AT	acceptor_loss	1.0000
22:29485721:AG:A	acceptor_gain	1.0000
22:29485722:G:GA	acceptor_gain	1.0000
22:29485722:GG:G	acceptor_gain	1.0000
22:29485722:GGA:G	acceptor_gain	1.0000
22:29485722:GGAA:G	acceptor_gain	1.0000
22:29485844:ACAG:A	donor_loss	1.0000
22:29485845:CAGG:C	donor_loss	1.0000
22:29485846:AGG:A	donor_loss	1.0000
22:29485848:G:C	donor_loss	1.0000
22:29485849:T:G	donor_loss	1.0000
22:29481139:TTCCG:T	donor_gain	0.9900

AlphaMissense

6627 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000146037 (22:29487317 C>T), RS1000249123 (22:29486154 G>A), RS1000283807 (22:29480831 G>A,C), RS1000756943 (22:29481143 G>C,T), RS1000986394 (22:29480366 G>A), RS1001084559 (22:29486378 C>T), RS1001294237 (22:29480212 G>A,T), RS1001622701 (22:29485146 A>G), RS1001634488 (22:29491377 G>A), RS1001826725 (22:29488822 T>C,G), RS1001904677 (22:29485384 T>C,G), RS1001953875 (22:29482905 A>C,G), RS1002065392 (22:29480736 G>A), RS1003032258 (22:29483960 G>A,C), RS1003119554 (22:29479532 T>C)

Disease associations

OMIM: gene MIM:162230 | disease phenotypes: MIM:616924, MIM:105400, MIM:606071

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2CC	Definitive	Autosomal dominant
amyotrophic lateral sclerosis	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	AD
Charcot-Marie-Tooth disease axonal type 2CC	Definitive	AD

Mondo (5): Charcot-Marie-Tooth disease axonal type 2CC (MONDO:0014836), amyotrophic lateral sclerosis type 1 (MONDO:0007103), amyotrophic lateral sclerosis (MONDO:0004976), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease axonal type 2C (MONDO:0011633)

Orphanet (2): Amyotrophic lateral sclerosis (Orphanet:803), Autosomal dominant Charcot-Marie-Tooth disease type 2C (Orphanet:99937)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001761	Pes cavus
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002021	Pyloric stenosis
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002398	Degeneration of anterior horn cells
HP:0002463	Language impairment
HP:0002495	Impaired vibratory sensation

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C531617	Amyotrophic lateral sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

66 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	9
Tretinoin	affects expression, increases expression	4
mercuric bromide	decreases expression, affects cotreatment	2
Decitabine	affects expression, decreases expression, decreases reaction	2
Estradiol	affects expression, affects binding, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
mipafox	decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	increases expression	1
cypermethrin	increases expression	1
sodium arsenite	decreases reaction, decreases expression	1
butyraldehyde	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
tri-o-cresyl phosphate	decreases reaction, decreases expression	1
3-methyladenine	decreases expression, decreases reaction	1
Ashwagandha	decreases expression, decreases reaction	1
hydroquinone	decreases expression	1
tryptanthrine	increases expression	1
cyfluthrin	increases expression	1
monoisoamyl-2,3-dimercaptosuccinate	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
ormosil	affects binding, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YH	Abcam HeLa NEFH KO	Cancer cell line	Female

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS