IFIH1
Chr 2ADARinterferon induced with helicase C domain 1
Also known as: AGS7, Hlcd, IDDM19, IMD95, MDA-5, MDA5, RLR-2, SGMRT1
IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
379 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 1 | 0 | 1 |
Likely Pathogenic | 1 | 0 | 0 | 0 | 1 |
VUS | 13 | 202 | 26 | 2 | 243 |
Likely Benign | 10 | 1 | 53 | 67 | 131 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 2 | |||
| Total | 24 | 203 | 81 | 69 | 379 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →IFIH1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
Gene2Phenotype Curations
Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Exploratory Clinical Study of CNCT19 Anti CD19 Cell Therapy in the Treatment of Refractory Autoimmune Diseases
RECRUITINGImmune Function and the Progression to T1D
RECRUITINGAssociations Between Dental Anomalies and Ocular, Cutaneous and Skin Appendages Features
NOT YET RECRUITINGMicroecology and Immunity in Patients With Anti-MDA5 Antibody Positive Dermatomyositis and Interstitial Lung Disease
RECRUITINGExternal Resources
Links to major genomics databases and tools