RNASEH2A

Chr 19

ribonuclease H2 subunit A

Also known as: AGS4, RNASEHI, RNHIA, RNHL

NCBI Gene: 10535 ENSG00000104889 UniProt: O75792

RNASEH2A encodes the catalytic subunit of RNase HII, an endonuclease that degrades RNA in RNA:DNA hybrids and excises single ribonucleotides from DNA duplexes during DNA replication. Mutations cause Aicardi-Goutières syndrome, an autosomal recessive neuroinflammatory disorder characterized by progressive microcephaly, psychomotor retardation, intracranial calcifications, and elevated interferon-alpha levels in cerebrospinal fluid. The gene shows low constraint to loss-of-function variation (pLI 0.004, LOEUF 0.88).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.88

Clinical Summary— RNASEH2A

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Gene-Disease Validity (ClinGen)

RNASEH2A-related type 1 interferonopathy · ARDefinitive

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

45 unique Pathogenic / Likely Pathogenic· 213 VUS of 565 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RNASEH2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.88LOEUF

pLI 0.004

Z-score 1.88

OE 0.45 (0.24–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.19Z-score

OE missense 0.96 (0.85–1.09)

171 obs / 178.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.24–0.88)

0≤0.351.4

Missense OE?0.96 (0.85–1.09)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 6 / 13.5Missense obs/exp: 171 / 178.2Syn Z: -0.59

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRNASEH2A-related Aicardi-Goutieres syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.4578th %ile

LOF

0.3068th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

565 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic25

VUS213

Likely Benign254

Benign21

Conflicting17

Pathogenic

Likely Pathogenic

213

VUS

254

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	2	1	1	20
Likely Pathogenic	16	7	1	1	25
VUS	5	186	19	3	213
Likely Benign	0	5	115	134	254
Benign	0	0	18	3	21
Conflicting	—				17
Total	37	200	154	142	550

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap RNASEH2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →