ADAR

Chr 1ARAD

adenosine deaminase RNA specific

Also known as: ADAR1, AGS6, DRADA, DSH, DSRAD, G1P1, IFI-4, IFI4

NCBI Gene: 103 ENSG00000160710 UniProt: P55265 OMIM: 146920

This gene encodes an enzyme that catalyzes adenosine-to-inosine RNA editing in double-stranded RNA, which can alter protein sequences, RNA splicing, and RNA stability. Mutations cause Aicardi-Goutières syndrome 6, a severe early-onset encephalopathy with neuroinflammation, and dyschromatosis symmetrica hereditaria, a skin pigmentation disorder. The gene shows both autosomal recessive and autosomal dominant inheritance patterns depending on the associated phenotype.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismAR/ADLOEUF 0.422 OMIM phenotypes

Clinical Summary— ADAR

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.42LOEUF

pLI 0.026

Z-score 4.78

OE 0.26 (0.17–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.27Z-score

OE missense 0.75 (0.70–0.81)

502 obs / 667.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.26 (0.17–0.42)

0≤0.351.4

Missense OE0.75 (0.70–0.81)

0≤0.61.4

Synonymous OE1.13

0≤1.21.6

LoF obs/exp: 13 / 49.2Missense obs/exp: 502 / 667.1Syn Z: -1.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveADAR-related dyschromatosis symmetrica hereditariaLOFAD

definitiveADAR-related Aicardi-Goutieres syndrome associated with a type I interferon signatureOTHERAD

definitiveADAR-related Aicardi-Goutieres syndrome associated with a type I interferon signatureLOFAR

0.5771th %ile

GOF

0.4875th %ile

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.42

DN1 literature citation

Literature Evidence

DNThe proximity of Gly1007 to the RNA backbone, and the possibility for an arginine residue to make polyvalent interactions there, suggests a mechanism whereby Arg1007 might confer a dominant-negative effect: by binding more tightly to RNA, the mutant protein could act as a competitive inhibitor of wiPMID:23001123

LOFTwo novel mutations and evidence for haploinsufficiency of the ADAR gene in dyschromatosis symmetrica hereditaria.PMID:16536805

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