Amyotrophic lateral sclerosis: genes and variants

Genes linked to Amyotrophic lateral sclerosis

• SOD1: Superoxide dismutase [Cu-Zn]

  It detoxifies superoxide radicals in the cytosol and mitochondrial intermembrane space, limiting oxidative injury. Pathogenic variants cause amyotrophic lateral sclerosis mainly through toxic properties of mutant protein rather than simple loss of antioxidant activity.

  104 disease-causing and 50 uncertain variants in SOD1 are linked to Amyotrophic lateral sclerosis.

• FUS: RNA-binding protein FUS

  It coordinates transcription, RNA processing, transport, and stress-granule dynamics and can shuttle between nucleus and cytoplasm. Pathogenic variants can cause amyotrophic lateral sclerosis through disturbed RNA and protein homeostasis and are also associated with frontotemporal degeneration.

  18 disease-causing and 108 uncertain variants in FUS are linked to Amyotrophic lateral sclerosis.

• TARDBP: TAR DNA-binding protein 43

  TDP-43 is an RNA-binding protein that regulates RNA processing, splicing, stability, and transport. Its normal activity supports neuronal and muscle cells, while abnormal TDP-43 accumulation is closely associated with amyotrophic lateral sclerosis and frontotemporal degeneration.

  12 disease-causing and 9 uncertain variants in TARDBP are linked to Amyotrophic lateral sclerosis.

• SETX: Helicase senataxin

  It resolves RNA-DNA hybrids and supports transcription termination, RNA processing, and genome stability, particularly in long-lived neurons. Different pathogenic mechanisms cause ataxia with oculomotor apraxia type 2 or juvenile amyotrophic lateral sclerosis type 4.

  6 disease-causing and 603 uncertain variants in SETX are linked to Amyotrophic lateral sclerosis.

• OPTN: Optineurin

  It serves as an adaptor in selective autophagy, vesicle trafficking, and inflammatory signaling and helps target damaged mitochondria or protein aggregates for clearance. Pathogenic variants can cause amyotrophic lateral sclerosis or certain glaucomas depending on the mechanism.

  3 disease-causing and 143 uncertain variants in OPTN are linked to Amyotrophic lateral sclerosis.

• UBQLN2: Ubiquilin-2

  It shuttles ubiquitinated proteins toward proteasomal or autophagic degradation and helps maintain protein quality in neurons. Dominant X-linked variants can cause amyotrophic lateral sclerosis with or without frontotemporal dementia through impaired proteostasis.

  1 disease-causing and 90 uncertain variants in UBQLN2 are linked to Amyotrophic lateral sclerosis.

• ERBB4: Receptor tyrosine-protein kinase erbB-4

  It transduces neuregulin and other EGF-family signals important for neural, cardiac, and mammary development. Altered signaling or somatic variants occur in several cancers and have also been studied in neurodevelopmental disease.

  1 disease-causing and 25 uncertain variants in ERBB4 are linked to Amyotrophic lateral sclerosis.

• SQSTM1: Sequestosome-1

  SQSTM1, also called p62, is an adapter that connects ubiquitinated cargo to autophagosomes for selective autophagy. It also influences the NRF2 cytoprotective pathway and endosomal organization, and SQSTM1 variants are associated with Paget disease of bone and neurodegeneration.

  0 disease-causing and 1 uncertain variants in SQSTM1 are linked to Amyotrophic lateral sclerosis.

• KIF5A: Kinesin heavy chain isoform 5A

  It drives anterograde transport of organelles and proteins along axonal microtubules and is especially important in long motor neurons. Pathogenic variants can cause hereditary spastic paraplegia, axonal Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis depending on the affected region and mechanism.

  0 disease-causing and 5 uncertain variants in KIF5A are linked to Amyotrophic lateral sclerosis.

• HNRNPA1: Heterogeneous nuclear ribonucleoprotein A1

  It regulates pre-mRNA splicing, RNA transport, translation, and stress-granule dynamics through RNA binding and reversible self-assembly. Rare pathogenic variants can cause multisystem proteinopathy, amyotrophic lateral sclerosis, or related neuromuscular degeneration through altered RNA and protein homeostasis.

  0 disease-causing and 1 uncertain variants in HNRNPA1 are linked to Amyotrophic lateral sclerosis.

• VCP: Transitional endoplasmic reticulum ATPase

  It uses ATP to extract ubiquitinated proteins from complexes or membranes for recycling or degradation and is central to proteostasis, ER-associated degradation, and autophagy. Dominant pathogenic variants cause multisystem proteinopathy with inclusion-body myopathy, Paget disease, frontotemporal dementia, or ALS.

  0 disease-causing and 0 uncertain variants in VCP are linked to Amyotrophic lateral sclerosis.

• C9ORF72: Guanine nucleotide exchange factor C9orf72

  It participates in endolysosomal trafficking, autophagy, and immune regulation through complexes with SMCR8 and WDR41. A large GGGGCC repeat expansion causes the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia.

  0 disease-causing and 0 uncertain variants in C9ORF72 are linked to Amyotrophic lateral sclerosis.

• SCN10A: Sodium channel protein type 10 subunit alpha

  The protein forms Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channel found in excitable membranes. It helps generate sensory-neuron electrical signals and is especially important in mechanisms of neuropathic pain and inherited episodic pain.

  0 disease-causing and 0 uncertain variants in SCN10A are linked to Amyotrophic lateral sclerosis.

• SCN1A: Sodium channel protein type 1 subunit alpha

  Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine.

  0 disease-causing and 0 uncertain variants in SCN1A are linked to Amyotrophic lateral sclerosis.

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  0 disease-causing and 0 uncertain variants in SCN2A are linked to Amyotrophic lateral sclerosis.

• SCN4A: Sodium channel protein type 4 subunit alpha

  Its rapid sodium current initiates and propagates skeletal-muscle action potentials. Gain- and loss-of-function variants cause disorders of muscle excitability including sodium-channel myotonia, paramyotonia congenita, periodic paralysis, and some congenital myopathies.

  0 disease-causing and 0 uncertain variants in SCN4A are linked to Amyotrophic lateral sclerosis.

• SCN8A: Sodium channel protein type 8 subunit alpha

  The protein forms Nav1.6, a voltage-gated sodium channel that sets the threshold and propagation of neuronal action potentials. It is widely important for neuronal excitability, and SCN8A variants are associated with developmental and epileptic encephalopathies.

  0 disease-causing and 0 uncertain variants in SCN8A are linked to Amyotrophic lateral sclerosis.

• SCN9A: Sodium channel protein type 9 subunit alpha

  The protein forms Nav1.7, a voltage-gated sodium channel that amplifies electrical signals in peripheral sensory neurons. Changes in Nav1.7 activity can produce either excessive pain or congenital insensitivity to pain, making SCN9A central to pain biology.

  0 disease-causing and 0 uncertain variants in SCN9A are linked to Amyotrophic lateral sclerosis.

• TBK1: Serine/threonine-protein kinase TBK1

  It activates IRF3 and related antiviral pathways after innate immune sensing and also participates in autophagy and cellular homeostasis. Loss-of-function variants can cause amyotrophic lateral sclerosis or frontotemporal dementia, while increased pathway activity can support inflammatory disease and some cancers.

  0 disease-causing and 0 uncertain variants in TBK1 are linked to Amyotrophic lateral sclerosis.

Weakly linked (only a few uncertain records): CHRNA4, ATXN2, CACNA1A, GRN and PON1.

Where Amyotrophic lateral sclerosis variants cluster

• TARDBP Interaction with UBQLN2 (positions 216–414): 11 of 12 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Amyotrophic lateral sclerosis

Showing 60 of 145.

Uncertain variants in Amyotrophic lateral sclerosis that look disease-causing

Which prediction tools work for Amyotrophic lateral sclerosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 86 out of 100
• PolyPhen-2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 81 out of 100
• EVE: 79 out of 100
• SIFT: 78 out of 100
• phyloP: 60 out of 100

Same protein, different disease

• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 is also caused by SETX variants; they fall mostly in different places as the Amyotrophic lateral sclerosis variants (17 disease-causing).

Diseases related to Amyotrophic lateral sclerosis

• Cardiac arrhythmia, also linked to SCN10A, SCN1A, SCN2A, SCN4A and 2 more
• Epilepsy, also linked to SCN10A, SCN1A, SCN2A, SCN4A and 2 more
• Focal epilepsy, also linked to SCN10A, SCN1A, SCN2A, SCN4A and 1 more
• Lennox-Gastaut syndrome, also linked to SCN10A, SCN1A, SCN2A, SCN8A and 1 more
• Frontotemporal dementia and/or amyotrophic lateral sclerosis, also linked to C9ORF72, SQSTM1, TBK1 and VCP
• Motor neuron disease, also linked to SOD1, TARDBP and TBK1
• Genetic developmental and epileptic encephalopathy, also linked to SCN1A, SCN2A and SCN8A
• Early-infantile DEE, also linked to SCN1A and SCN8A
• Hereditary spastic paraplegia, also linked to KIF5A and SETX
• Charcot-Marie-Tooth disease, also linked to KIF5A and VCP
• Seizures, benign familial infantile, 3, also linked to SCN2A and SCN8A
• Generalized epilepsy with febrile seizures plus, also linked to SCN1A and SCN9A

Frequently asked questions

Which genes are linked to Amyotrophic lateral sclerosis?

In CATVariant, Amyotrophic lateral sclerosis is linked to 19 analyzed proteins: SOD1 (Superoxide dismutase [Cu-Zn]), FUS (RNA-binding protein FUS), TARDBP (TAR DNA-binding protein 43), SETX (Helicase senataxin), OPTN (Optineurin), UBQLN2 (Ubiquilin-2) and 13 more.

How many genetic variants are linked to Amyotrophic lateral sclerosis?

1,502 variants: 145 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,039 are of uncertain significance or have conflicting reports.

Which uncertain variants in Amyotrophic lateral sclerosis look disease-causing?

9 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SOD1 R116C, SOD1 R116H, SOD1 A90T, SOD1 Q23H and TARDBP G295R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Amyotrophic lateral sclerosis?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 104 disease-causing and 116 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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