IFIH1

Chr 2

interferon induced with helicase C domain 1

Also known as: AGS7, Hlcd, IDDM19, IMD95, MDA-5, MDA5, RLR-2, SGMRT1

NCBI Gene: 64135 ENSG00000115267 UniProt: Q9BYX4

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.55

Clinical Summary— IFIH1

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Gene-Disease Validity (ClinGen)

IFIH1-related type 1 interferonopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

42 unique Pathogenic / Likely Pathogenic· 955 VUS of 1760 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — IFIH1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.55LOEUF

pLI 0.000

Z-score -1.57

OE 1.25 (1.01–1.55)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.79Z-score

OE missense 1.10 (1.02–1.17)

586 obs / 534.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.25 (1.01–1.55)

0≤0.351.4

Missense OE?1.10 (1.02–1.17)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 59 / 47.3Missense obs/exp: 586 / 534.7Syn Z: -1.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveIFIH1-related Aicardi-Goutieres syndromeOTHERAD

strongIFIH1-related Singleton-Merten syndromeGOFAD

This gene — mechanism propensity

0.6064th %ile

GOF

0.6052th %ile

LOF

0.3164th %ile

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.

GOF1 literature citation · 86% of P/LP are missense

LOF1 literature citation

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

GOFAutosomal dominant IFIH1 gain-of-function mutations cause Aicardi-Goutieres syndrome.1

LOFWe highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1760 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic17

VUS955

Likely Benign576

Benign69

Conflicting97

Pathogenic

Likely Pathogenic

955

VUS

576

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	25	0	0	25
Likely Pathogenic	6	11	0	0	17
VUS	92	803	54	6	955
Likely Benign	39	95	174	268	576
Benign	0	4	56	9	69
Conflicting	—				97
Total	137	938	284	283	1,739

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap IFIH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →