Arthrogryposis multiplex congenita: genes and variants
Arthrogryposis multiplex congenita is linked to 4 analyzed proteins (SCN4A, SCN8A, NEB and RYR1). 2 DNA variants are known to cause it; 16 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Arthrogryposis multiplex congenita 6
Genes linked to Arthrogryposis multiplex congenita
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.
1 disease-causing and 0 uncertain variants in SCN4A are linked to Arthrogryposis multiplex congenita.
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.
1 disease-causing and 0 uncertain variants in SCN8A are linked to Arthrogryposis multiplex congenita.
NEB: Nebulin
It spans much of the skeletal-muscle thin filament and acts as a molecular scaffold that helps specify filament length and optimize actin-myosin interaction. Biallelic pathogenic variants are a major cause of nemaline myopathy and related congenital myopathies.
0 disease-causing and 14 uncertain variants in NEB are linked to Arthrogryposis multiplex congenita.
RYR1: Ryanodine receptor 1
It releases calcium from the skeletal-muscle sarcoplasmic reticulum when Cav1.1 senses membrane depolarization, directly coupling excitation to contraction. Pathogenic variants cause malignant-hyperthermia susceptibility and a broad spectrum of congenital RYR1-related myopathies.
0 disease-causing and 0 uncertain variants in RYR1 are linked to Arthrogryposis multiplex congenita.
Weakly linked (only a few uncertain records): RYR3.
Known disease-causing variants in Arthrogryposis multiplex congenita
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| SCN4A L673P | 673 | II | Disease-causing (★★) |
| SCN8A I240T | 240 | I | Disease-causing (★★) |
Same protein, different disease
- Hyperkalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (62 disease-causing).
- Paramyotonia congenita of Von Eulenburg is also caused by SCN4A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (15 disease-causing).
- Potassium-aggravated myotonia is also caused by SCN4A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (14 disease-causing).
- Hypokalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (11 disease-causing).
- Congenital myopathy 22A, classic is also caused by SCN4A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (8 disease-causing).
- Early-infantile DEE is also caused by SCN8A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (90 disease-causing).
- Cognitive impairment with or without cerebellar ataxia is also caused by SCN8A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (22 disease-causing).
- Seizures, benign familial infantile, 3 is also caused by SCN8A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (12 disease-causing).
- Complex neurodevelopmental disorder is also caused by SCN8A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (8 disease-causing).
- Autosomal recessive inheritance is also caused by SCN8A variants; they fall mostly in different places as the Arthrogryposis multiplex congenita variants (3 disease-causing).
Diseases related to Arthrogryposis multiplex congenita
- Fetal akinesia deformation sequence, also linked to RYR1, SCN4A and SCN8A
- Amyotrophic lateral sclerosis, also linked to SCN4A and SCN8A
- Cardiac arrhythmia, also linked to SCN4A and SCN8A
- Epilepsy, also linked to SCN4A and SCN8A
- Early-infantile DEE, also linked to SCN8A
- Seizures, benign familial infantile, 3, also linked to SCN8A
- Sotos syndrome, also linked to SCN4A
- Hyperkalemic periodic paralysis, also linked to SCN4A
- Complex neurodevelopmental disorder, also linked to SCN8A
- Hypokalemic periodic paralysis, also linked to SCN4A
- Congenital myasthenic syndrome 17, also linked to SCN4A
- Cognitive impairment with or without cerebellar ataxia, also linked to SCN8A
Frequently asked questions
Which genes are linked to Arthrogryposis multiplex congenita?
In CATVariant, Arthrogryposis multiplex congenita is linked to 4 analyzed proteins: SCN4A (Sodium channel protein type 4 subunit alpha), SCN8A (Sodium channel protein type 8 subunit alpha), NEB (Nebulin) and RYR1 (Ryanodine receptor 1).
How many genetic variants are linked to Arthrogryposis multiplex congenita?
28 variants: 2 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 16 are of uncertain significance or have conflicting reports.
Which uncertain variants in Arthrogryposis multiplex congenita look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
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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