RNASEH2A

Chr 19AR

ribonuclease H2 subunit A

Also known as: AGS4, RNASEHI, RNHIA, RNHL

NCBI Gene: 10535ENSG00000104889UniProt: O75792

The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]

Primary Disease Associations & Inheritance

Aicardi-Goutieres syndrome 4MIM #610333
AR
576
ClinVar variants
64
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RNASEH2A
🧬
Gene-Disease Validity (ClinGen)
RNASEH2A-related type 1 interferonopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 219 VUS of 576 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.88LOEUF
pLI 0.004
Z-score 1.88
OE 0.45 (0.24–0.88)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.19Z-score
OE missense 0.96 (0.85–1.09)
171 obs / 178.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.45 (0.24–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.85–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 6 / 13.5Missense obs/exp: 171 / 178.2Syn Z: -0.59

ClinVar Variant Classifications

576 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic27
VUS219
Likely Benign255
Benign21
Conflicting17
37
Pathogenic
27
Likely Pathogenic
219
VUS
255
Likely Benign
21
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
2
24
1
37
Likely Pathogenic
14
7
5
1
27
VUS
4
182
30
3
219
Likely Benign
0
6
115
134
255
Benign
0
0
18
3
21
Conflicting
—17
Total28197192142576

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

View in ClinVar →

Protein Context — Lollipop Plot

RNASEH2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RNASEH2A-related Aicardi-Goutieres syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Aicardi-Goutieres syndrome 4

MIM #610333

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RNASEH2A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Aicardi-Goutières syndrome: A monogenic type I interferonopathy.
Liu A et al.·Scand J Immunol
2023Review
Clinical and molecular phenotype of Aicardi-Goutieres syndrome.
Rice G et al.·Am J Hum Genet
2007
Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
Crow YJ et al.·Am J Med Genet A
2015
Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.
Rice GI et al.·Lancet Neurol
2013
Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières Syndrome and Beyond.
Livingston JH et al.·Neuropediatrics
2016Review
Systemic complications of Aicardi Goutières syndrome using real-world data.
Peixoto de Barcelos I et al.·Mol Genet Metab
2024
Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus.
Sayadi A et al.·Lupus Sci Med
2025
De novo variants in immune regulatory genes in Down syndrome regression disorder.
Jafarpour S et al.·J Neurol
2024
RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells.
Sugawara S et al.·Commun Biol
2022
PNPT1 mutations may cause Aicardi-Goutières-Syndrome.
Bamborschke D et al.·Brain Dev
2021Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools