Multiple sclerosis: genes and variants

Genes linked to Multiple sclerosis

• CYP27B1: 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial

  The kidney enzyme that converts 25-hydroxyvitamin D into active 1,25-dihydroxyvitamin D. Biallelic variants cause vitamin D-dependent rickets type 1A.

  2 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CYP27B1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• TNFRSF1A: Tumor necrosis factor receptor superfamily member 1A

  It mediates many inflammatory and cell-death responses to TNF through NF-kappaB, MAPK, and death-domain signaling. Dominant pathogenic variants that alter receptor handling cause TNF receptor-associated periodic syndrome, an inherited autoinflammatory disease.

  1 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in TNFRSF1A have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• AURKB: Aurora kinase B

  It controls chromosome alignment, kinetochore-microtubule attachment, the spindle checkpoint, and cytokinesis as part of the chromosomal passenger complex. Excess activity is common in proliferative cancers and can contribute to aneuploidy and treatment resistance.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in AURKB have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• AXL: Tyrosine-protein kinase receptor UFO

  Activation by GAS6 promotes cell survival, migration, immune modulation, and resistance to cellular stress. Persistent signaling is common in advanced cancers and can support epithelial-to-mesenchymal transition, metastasis, and resistance to targeted or immune therapies.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in AXL have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• CDK1: Cyclin-dependent kinase 1

  It is the central kinase that drives cells into mitosis and coordinates chromosome condensation, nuclear-envelope breakdown, spindle assembly, and other mitotic events. Because proliferating tumor cells depend on tightly regulated CDK1 activity, its pathway is extensively studied as an anticancer target.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CDK1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• CDK12: Cyclin-dependent kinase 12

  It promotes transcription of long DNA-repair and genome-maintenance genes through RNA-polymerase-II phosphorylation. Loss-of-function alterations occur in prostate, ovarian, and other cancers and can create a characteristic pattern of genomic instability.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CDK12 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• CDK4: Cyclin-dependent kinase 4

  Together with D-type cyclins, it phosphorylates RB-family proteins and commits cells to progress from G1 toward DNA replication. Amplification or pathway activation is common in cancer, while rare activating germline variants predispose to familial melanoma.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CDK4 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• CDKN1C: Cyclin-dependent kinase inhibitor 1C

  It restrains embryonic and placental cell proliferation and is subject to parent-of-origin-specific genomic imprinting. Loss of maternal expression contributes to Beckwith-Wiedemann syndrome, whereas gain-of-function variants can cause growth-restriction syndromes such as IMAGe syndrome.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CDKN1C have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

  It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in HMGCR have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IFNAR1: Interferon alpha/beta receptor 1

  Together with IFNAR2, it detects type I interferons and activates JAK-STAT antiviral and immunoregulatory programs. Loss-of-function can impair antiviral defense, while excessive pathway activation contributes to interferon-driven inflammatory disease.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IFNAR1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IFNAR2: Interferon alpha/beta receptor 2

  It provides the high-affinity ligand-binding component of the type I interferon receptor complex and triggers antiviral JAK-STAT signaling with IFNAR1. Biallelic loss-of-function variants can predispose to severe viral infections, including critical COVID-19 in some individuals.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IFNAR2 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IL2RA: Interleukin-2 receptor subunit alpha

  It contributes to the high-affinity IL-2 receptor on activated T cells and regulatory T cells, supporting lymphocyte proliferation and immune tolerance. Loss-of-function variants can cause immunodeficiency with autoimmunity, while abnormal expression is therapeutically targeted in selected immune disorders.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL2RA have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IL2RB: Interleukin-2 receptor subunit beta

  It transmits signals from IL-2 and IL-15 that are essential for regulatory T cells, natural-killer cells, and memory lymphocytes. Biallelic pathogenic variants can cause combined immunodeficiency with prominent autoimmunity and defective immune regulation.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL2RB have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IL2RG: Cytokine receptor common subunit gamma

  It is the shared signaling chain used by receptors for several interleukins required for lymphocyte development and survival. Loss-of-function variants cause X-linked severe combined immunodeficiency with profound T-cell and natural-killer-cell deficiency.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL2RG have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• IL7R: Interleukin-7 receptor subunit alpha

  It transmits survival and developmental signals required for T-cell and lymphoid homeostasis. Biallelic loss-of-function variants cause T-cell-negative, B-cell-positive severe combined immunodeficiency, while somatic activating alterations occur in acute lymphoblastic leukemia.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL7R have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNA1: Potassium voltage-gated channel subfamily A member 1

  Its potassium current limits neuronal excitability and shapes action-potential repolarization, especially in axons and presynaptic terminals. Pathogenic variants classically cause episodic ataxia type 1 and can also produce epilepsy, myokymia, and related neurologic phenotypes.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNA1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNA2: Potassium voltage-gated channel subfamily A member 2

  Its current helps repolarize neuronal membranes and regulate action-potential firing and neurotransmitter release. Both loss- and gain-of-function variants can cause developmental and epileptic encephalopathy, often with ataxia, movement abnormalities, or intellectual disability.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNA2 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNB1: Potassium voltage-gated channel subfamily B member 1

  Its delayed-rectifier current contributes to neuronal repolarization and also participates in activity-dependent signaling complexes at the membrane. De novo pathogenic variants are an important cause of developmental and epileptic encephalopathy with intellectual disability and variable seizures.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNB1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNH2: Voltage-gated inwardly rectifying potassium channel KCNH2

  Its unusually rapid inactivation and slow deactivation shape the rapid delayed-rectifier current IKr, a major determinant of ventricular repolarization. Loss-of-function variants can prolong repolarization and cause long-QT syndrome, whereas gain-of-function variants can cause short-QT syndrome.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNH2 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNQ1: Potassium voltage-gated channel subfamily KQT member 1

  The protein forms the pore of a voltage-gated potassium channel that helps set electrical activity in heart muscle. Its partnerships with KCNE subunits also support normal function in the inner ear and other tissues, while KCNQ1 variants are linked to long-QT and short-QT syndromes.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNQ2: Potassium voltage-gated channel subfamily KQT member 2

  Together with KCNQ3, its slowly activating potassium current provides much of the neuronal M-current that suppresses repetitive firing. Pathogenic variants cause a spectrum from self-limited familial neonatal epilepsy to severe developmental and epileptic encephalopathy.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ2 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNQ3: Potassium voltage-gated channel subfamily KQT member 3

  Together with KCNQ2, its slowly activating current provides much of the neuronal M-current that suppresses repetitive firing. Pathogenic variants can cause self-limited neonatal epilepsy or more severe developmental and epileptic encephalopathy.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ3 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNQ4: Potassium voltage-gated channel subfamily KQT member 4

  Its potassium conductance is crucial for electrical homeostasis in cochlear outer hair cells and auditory pathways. Dominant pathogenic variants are a well-established cause of progressive nonsyndromic sensorineural hearing loss, classically DFNA2.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ4 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KCNQ5: Potassium voltage-gated channel subfamily KQT member 5

  Its slowly activating potassium current helps stabilize membrane excitability in neurons and smooth muscle. Pathogenic variants can cause neurodevelopmental disorders with intellectual disability and epilepsy, with both gain- and loss-of-function mechanisms reported.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ5 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• KEAP1: Kelch-like ECH-associated protein 1

  It continuously targets NRF2 for degradation under basal conditions but releases this brake when reactive electrophiles or oxidative stress modify KEAP1. Somatic loss-of-function variants can lock tumors into a persistent antioxidant state that promotes survival and treatment resistance.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KEAP1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• MS4A1: B-lymphocyte antigen CD20

  Its expression spans much of B-cell development and contributes to calcium signaling and B-cell activation. Its stable surface expression makes it a major therapeutic target for B-cell depletion in lymphoma, leukemia, and autoimmune disease.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in MS4A1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• NR3C1: Glucocorticoid receptor

  It converts glucocorticoid binding into transcriptional programs that regulate metabolism, stress responses, inflammation, and immune activity. Loss-of-function variants can cause glucocorticoid resistance, while excessive or prolonged signaling underlies many adverse effects of corticosteroid therapy.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in NR3C1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• PLK1: Serine/threonine-protein kinase PLK1

  It coordinates centrosome maturation, chromosome segregation, spindle function, and cytokinesis during mitosis. Many tumors overexpress PLK1 and depend on its activity for rapid proliferation, making it a prominent anticancer drug target.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PLK1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

• SMPD1: Sphingomyelin phosphodiesterase

  It hydrolyzes sphingomyelin to ceramide in lysosomes and participates in membrane-lipid turnover and stress signaling. Biallelic loss-of-function variants cause acid sphingomyelinase deficiency, including Niemann-Pick disease types A and B.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in SMPD1 have source records linked to Multiple sclerosis. Association strength is not clinical gene validity.

Weakly linked (only a few uncertain records): ITGB4.

ClinVar pathogenic and likely pathogenic variants linked to Multiple sclerosis

Same protein, different disease

• Vitamin D-dependent rickets, type 1A also has ClinVar records linked to CYP27B1 variants; they fall mostly in different places as the Multiple sclerosis variants (25 pathogenic / likely pathogenic).
• TNF receptor-associated periodic fever syndrome (TRAPS) also has ClinVar records linked to TNFRSF1A variants; they fall mostly in different places as the Multiple sclerosis variants (21 pathogenic / likely pathogenic).

Diseases related to Multiple sclerosis

• Alzheimer disease, also linked to AURKB, AXL, CDK1, CDK12 and 5 more
• Parkinson disease, also linked to AURKB, AXL, CDK1, CDK12 and 5 more
• Epilepsy, also linked to KCNQ1, KCNQ2, KCNQ3, KCNQ4 and 1 more
• Congenital myasthenic syndrome 17, also linked to KCNA1, KCNA2 and KCNQ4
• Multiple myeloma, also linked to IFNAR1, IFNAR2 and NR3C1
• Renal cell carcinoma, also linked to IL2RA, IL2RB and IL2RG
• Genetic developmental and epileptic encephalopathy, also linked to KCNA2, KCNB1 and KCNQ2
• Long QT syndrome, also linked to KCNH2 and KCNQ1
• Seizures, benign familial infantile, 3, also linked to KCNQ2 and KCNQ3
• Cardiac arrhythmia, also linked to KCNH2 and KCNQ1
• Type 2 diabetes mellitus, also linked to HMGCR and KCNQ1
• Short QT syndrome type 3, also linked to KCNH2 and KCNQ1

Frequently asked questions

Which genes have records linked to Multiple sclerosis?

This view contains 29 analyzed proteins: CYP27B1, TNFRSF1A, AURKB, AXL, CDK1 and 24 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.

What do the clinical classifications mean?

Linked records include 3 pathogenic or likely pathogenic variants, 1 variants of uncertain significance and 0 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.

Does the evidence score change a VUS classification?

No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.

Can I download the variant evidence?

Download the CSV for all 5 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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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