IFIH1

Chr 2ADAR

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 OMIM: 606951

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Aicardi-Goutieres syndrome 7MIM #615846

Immunodeficiency 95MIM #619773

Singleton-Merten syndrome 1MIM #182250

UniProtType 1 diabetes mellitus 19

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · IFIH1-related type 1 interferonopathy · AD · ClinGen 2024

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

116

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.55

LOEUF

GOF

Mechanism· G2P

📖

GeneReview available — IFIH1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in IFIH1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 39

1,426 rare PASS variants

Rare truncating (LoF)

1 in 190

261 rare PASS variants

Rare synonymous (reference)

1 in 86

507 rare PASS variants

Rare missense and truncating variants are carried at similar rates in IFIH1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 46	1 in 240
South Asian	~43k	1 in 43	1 in 120
Remaining (unassigned)	~30k	1 in 31	1 in 160
European (Finnish)	~27k	1 in 120	1 in 530
Admixed American	~22k	1 in 39	1 in 210
African / African American	~21k	1 in 42	1 in 230
East Asian	~20k	1 in 34	1 in 330
Ashkenazi Jewish	~13k	1 in 140	1 in 1,100
Middle Eastern	~2,884	1 in 33	1 in 160

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 16 coding exons well covered in gnomAD exomes; exons 8, 9, 10, 12 marginal. Genomes: all 16.? see exons ↓