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, an intracellular sensor that detects viral RNA and activates interferon-mediated antiviral immune responses. Mutations cause Aicardi-Goutières syndrome, immunodeficiency, and Singleton-Merten syndrome with both autosomal dominant and autosomal recessive inheritance patterns. The gene is extremely intolerant to loss-of-function variants (pLI near zero), indicating that complete loss of MDA5 function is typically incompatible with normal development.
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.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
IFIH1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Microecology and Immunity in Patients With Anti-MDA5 Antibody Positive Dermatomyositis and Interstitial Lung Disease
RECRUITINGImmune Function and the Progression to T1D
RECRUITINGAssociations Between Dental Anomalies and Ocular, Cutaneous and Skin Appendages Features
NOT YET RECRUITINGExploratory Clinical Study of CNCT19 Anti CD19 Cell Therapy in the Treatment of Refractory Autoimmune Diseases
RECRUITINGExternal Resources
Links to major genomics databases and tools