RNASEH2C

Chr 11

ribonuclease H2 subunit C

Also known as: AGS3, AYP1

NCBI Gene: 84153ENSG00000172922UniProt: Q8TDP1

This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtAicardi-Goutieres syndrome 3
294
ClinVar variants
5
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— RNASEH2C
🧬
Gene-Disease Validity (ClinGen)
RNASEH2C-related type 1 interferonopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 123 VUS of 294 total submissions
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?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.
1.47LOEUF
pLI 0.005
Z-score 0.79
OE 0.65 (0.32–1.47)
Tolerant

Highly tolerant — LoF variants common in population

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.
-0.92Z-score
OE missense 1.26 (1.09–1.47)
122 obs / 96.6 exp
Tolerant

Tolerant to missense variation

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.0.65 (0.32–1.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.26 (1.09–1.47)
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.1.28
0≤1.21.6
LoF obs/exp: 4 / 6.1Missense obs/exp: 122 / 96.6Syn Z: -1.41

ClinVar Variant Classifications

294 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic2
VUS123
Likely Benign163
Conflicting3
3
Pathogenic
2
Likely Pathogenic
123
VUS
163
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
3
0
3
Likely Pathogenic
0
0
2
0
2
VUS
7
106
10
0
123
Likely Benign
0
2
69
92
163
Benign
0
0
0
0
0
Conflicting
—3
Total71088492294

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

View in ClinVar →

Protein Context — Lollipop Plot

RNASEH2C · protein map & ClinVar variants

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

Gene2Phenotype Curations

RNASEH2C-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

OMIM

No OMIM entries found.

📖
GeneReview available — RNASEH2C
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
Trio Whole Exome Sequencing in Chinese Childhood-Onset Lupus Reveals Novel Candidate Genes.
Ma J et al.·Arthritis Rheumatol
2025
RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutières syndrome 3.
Wang Q et al.·Clin Genet
2023Cohort
[Clinical report and genetic analysis of a child with Aicardi-Goutières syndrome type 3 due to compound heterozygous variants of RNASEH2C gene].
Liu J et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2023
Contributions of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of the human RNase H2 complex.
Chon H et al.·Nucleic Acids Res
2009
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