RNASEH2A

Summary

RNASEH2A (ribonuclease H2 subunit A, HGNC:18518) is a protein-coding gene on chromosome 19p13.13, encoding Ribonuclease H2 subunit A (O75792). Catalytic subunit of RNase HII, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. It is a selective cancer dependency (DepMap: 24.3% of cell lines).

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.

Source: NCBI Gene 10535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RNASEH2A-related type 1 interferonopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 490 total — 17 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 88
• Cancer dependency (DepMap): dependent in 24.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_006397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18518
Approved symbol	RNASEH2A
Name	ribonuclease H2 subunit A
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	RNASEHI, RNHIA, RNHL, AGS4
Ensembl gene	ENSG00000104889
Ensembl biotype	protein_coding
OMIM	606034
Entrez	10535

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000221486, ENST00000590121, ENST00000590279, ENST00000593017, ENST00000643757, ENST00000646769, ENST00000926044, ENST00000926045

RefSeq mRNA: 1 — MANE Select: NM_006397 NM_006397

CCDS: CCDS12282

Canonical transcript exons

ENST00000221486 — 8 exons

Exon	Start	End
ENSE00001265301	12806584	12806800
ENSE00003469311	12810317	12810404
ENSE00003472728	12807008	12807079
ENSE00003515791	12807419	12807506
ENSE00003520689	12810071	12810208
ENSE00003593437	12807206	12807329
ENSE00003677620	12813083	12813206
ENSE00003822247	12813328	12813640

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 94.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1978 / max 311.3314, expressed in 1790 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174029	29.9191	1676
174028	15.2787	1729

Top tissues by expression

140 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	94.83	gold quality
embryo	UBERON:0000922	94.82	gold quality
ventricular zone	UBERON:0003053	94.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.04	gold quality
mucosa of transverse colon	UBERON:0004991	89.05	gold quality
granulocyte	CL:0000094	86.28	gold quality
stromal cell of endometrium	CL:0002255	86.03	gold quality
placenta	UBERON:0001987	85.76	gold quality
cortical plate	UBERON:0005343	85.64	gold quality
lymph node	UBERON:0000029	85.15	gold quality
esophagus mucosa	UBERON:0002469	84.51	gold quality
bone element	UBERON:0001474	83.57	gold quality
bone marrow	UBERON:0002371	83.57	gold quality
spleen	UBERON:0002106	82.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.73	gold quality
rectum	UBERON:0001052	82.58	gold quality
lower esophagus mucosa	UBERON:0035834	82.53	gold quality
right testis	UBERON:0004534	82.21	gold quality
left testis	UBERON:0004533	82.13	gold quality
vermiform appendix	UBERON:0001154	82.10	gold quality
testis	UBERON:0000473	81.95	gold quality
duodenum	UBERON:0002114	81.95	gold quality
ectocervix	UBERON:0012249	81.67	gold quality
right uterine tube	UBERON:0001302	80.96	gold quality
islet of Langerhans	UBERON:0000006	80.71	gold quality
blood	UBERON:0000178	80.52	gold quality
skin of leg	UBERON:0001511	80.35	gold quality
skin of abdomen	UBERON:0001416	80.34	gold quality
zone of skin	UBERON:0000014	80.26	gold quality
smooth muscle tissue	UBERON:0001135	80.11	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	37.66
E-HCAD-13	yes	21.87
E-GEOD-125970	yes	16.06
E-ANND-3	yes	5.57
E-GEOD-99795	no	282.85
E-MTAB-7303	no	139.87
E-CURD-112	no	3.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting RNASEH2A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-597-3P	96.46	68.03	1035

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 24.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• analysis of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome (PMID:21454563)
• study identified two synonymous variants in RNASEH2A that result in loss of RNase H2 enzyme function and the consequent Aicardi-Goutieres syndrome phenotype (PMID:23592335)
• RNase H2 complex is assembled in the cytosol and imported into the nucleus in an RNase H2B-dependent manner. (PMID:24986920)
• Studies indicate that most antiviral-defense systems involve RNase H-like enzymes destroying invading nucleic acids, RNA, or DNA. (PMID:25703292)
• RNaseH2A may be involved in human gliomagenesis. (PMID:27176716)
• This study reviewed that Neurologic Phenotypes Associated with Mutations in RNASEH2A in patients with Aicardi-Goutieres Syndrome. (PMID:27643693)
• The expression levels of RNASEH2A, CDK1, and CD151 and their combination could predict the survival of renal cell carcinoma patients. (PMID:29843367)
• ATR inhibition may be beneficial for cancer patients with reduced levels of RNASEH2. (PMID:30532030)
• The authors predict that the induction of expression of RNASEH2A via human papillomavirus 16 E7 and E2F1 may promote DNA replication and cancer cell proliferation. (PMID:30696738)
• Germline variation of Ribonuclease H2 genes in ovarian cancer patients. (PMID:33353557)
• Hypoxia-induced RNASEH2A limits activation of cGAS-STING signaling in HCC and predicts poor prognosis. (PMID:34165025)
• Long noncoding RNA LINC01287 promotes proliferation and inhibits apoptosis of lung adenocarcinoma cells via the miR-3529-5p/RNASEH2A axis under the competitive endogenous RNA pattern. (PMID:34254728)
• Decrease in RNase HII and Accumulation of lncRNAs/DNA Hybrids: A Causal Implication in Psoriasis? (PMID:35327560)
• Depletion of RNASEH2 Activity Leads to Accumulation of DNA Double-strand Breaks and Reduced Cellular Survivability in T Cell Leukemia. (PMID:35500843)
• RNase H2, mutated in Aicardi-Goutieres syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation. (PMID:35618715)
• RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells. (PMID:36577784)
• Ribonuclease H2 Subunit A Preserves Genomic Integrity and Promotes Prostate Cancer Progression. (PMID:36923313)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnaseh2a	ENSDARG00000018891
mus_musculus	Rnaseh2a	ENSMUSG00000052926
rattus_norvegicus	Thsd8	ENSRNOG00000003504
drosophila_melanogaster	CG13690	FBGN0031252
caenorhabditis_elegans		WBGENE00004383

Protein

Protein identifiers

Ribonuclease H2 subunit A — O75792 (reviewed: O75792)

Alternative names: Aicardi-Goutieres syndrome 4 protein, RNase H(35), Ribonuclease HI large subunit, Ribonuclease HI subunit A

All UniProt accessions (3): O75792, A0A2R8Y606, A0A2R8Y658

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of RNase HII, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging-strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes.

Subunit / interactions. The RNase H2 complex is a heterotrimer composed of the catalytic subunit RNASEH2A and the non-catalytic subunits RNASEH2B and RNASEH2C.

Subcellular location. Nucleus.

Disease relevance. Aicardi-Goutieres syndrome 4 (AGS4) [MIM:610333] A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Manganese or magnesium. Binds 1 divalent metal ion per monomer in the absence of substrate. May bind a second metal ion after substrate binding.

Similarity. Belongs to the RNase HII family. Eukaryotic subfamily.

RefSeq proteins (1): NP_006388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001352	RNase_HII/HIII	Family
IPR004649	RNase_H2_suA	Family
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR023160	RNase_HII_hlx-loop-hlx_cap_dom	Homologous_superfamily
IPR024567	RNase_HII/HIII_dom	Domain
IPR036397	RNaseH_sf	Homologous_superfamily

Pfam: PF01351

Enzyme classification (BRENDA):

• EC 3.1.26.4 — ribonuclease H (BRENDA: 55 organisms, 293 substrates, 156 inhibitors, 81 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

24 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
RNA*DNA HYBRID	0.0001–0.0084	9
DNA-RNA-DNA HYBRID	0.0011–0.0078	7
RNA-DNA HETERODUPLEX	0.0001–0.2	7
RNA-DNA*DNA HYBRID	0.0001–0.0036	5
M13 DNA/RNA HYBRID	0.0004–0.0014	4
RNA-DNA HYBRID	0.0011–0.0028	4
D14R1D3:DNA18	—	3
M13 DNA-RNA HYBRID	0.071–0.26	3
POLY(RADT)	0.0005–0.0019	3
RNA18:DNA18	0.0001–0.0002	3
DNA-RNA HYBRID DUPLEX	—	2
M13 DNA/RNA	0.0005–0.0011	2
5’-(6-CARBOXY-FLUORESCEIN)-CGGAGAUGACGG-3’/5’-CC	0.0004	1
DNA-(1’,2’-METHYLENE-BRIDGED AZETIDINE-T)-ANTISE	0.0001	1
DNA-(2’-ALKOXY-1’,2’-METHYLENE-BRIDGED AZETIDINE	0.0002	1

UniProt features (53 total): sequence variant 13, helix 12, strand 10, mutagenesis site 6, modified residue 5, binding site 3, chain 1, domain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3PUF	X-RAY DIFFRACTION	3.1
3P56	X-RAY DIFFRACTION	4.06
8YJZ	ELECTRON MICROSCOPY	5.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75792-F1	87.69	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 34; 35; 141

Post-translational modifications (5): 1, 204, 216, 257, 277

Mutagenesis-validated functional residues (6):

Position	Phenotype
67	loss of enzyme activity.
69	strongly reduced enzyme activity.
112	reduced enzyme activity.
210	strongly reduced enzyme activity.
210	loss of enzyme activity.
240	strongly reduced enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 373 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GNF2_CKS1B, MODULE_52, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_NUCLEASE_ACTIVITY, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, PUJANA_CHEK2_PCC_NETWORK, MODULE_118, GOMF_RNA_ENDONUCLEASE_ACTIVITY, BLALOCK_ALZHEIMERS_DISEASE_UP, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN

GO Biological Process (5): DNA replication (GO:0006260), mismatch repair (GO:0006298), RNA catabolic process (GO:0006401), DNA replication, removal of RNA primer (GO:0043137), RNA metabolic process (GO:0016070)

GO Molecular Function (9): RNA binding (GO:0003723), RNA-DNA hybrid ribonuclease activity (GO:0004523), RNA nuclease activity (GO:0004540), metal ion binding (GO:0046872), nucleic acid binding (GO:0003676), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), ribonuclease H2 complex (GO:0032299), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclease activity	2
binding	2
cellular anatomical structure	2
DNA metabolic process	1
DNA biosynthetic process	1
DNA repair	1
RNA metabolic process	1
nucleic acid catabolic process	1
DNA replication	1
RNA catabolic process	1
nucleic acid metabolic process	1
nucleic acid binding	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
catalytic activity, acting on RNA	1
cation binding	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2991 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASEH2A	RNASEH2B	Q5TBB1	999
RNASEH2A	RNASEH2C	Q8TDP1	999
RNASEH2A	SAMHD1	Q9Y3Z3	967
RNASEH2A	TREX1	Q9NSU2	883
RNASEH2A	FEN1	P39748	762
RNASEH2A	ADAR	P55265	742
RNASEH2A	EXO1	Q9UQ84	694
RNASEH2A	RNASEH1	O60930	691
RNASEH2A	IFIH1	Q9BYX4	667
RNASEH2A	TOP2A	P11388	649
RNASEH2A	TOP1MT	Q969P6	630
RNASEH2A	IFNA13	P01562	627
RNASEH2A	PRIM2	P49643	610
RNASEH2A	PALB2	Q86YC2	605
RNASEH2A	TOP1	P11387	577

IntAct

34 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
RNASEH2B	RNASEH2A	psi-mi:“MI:0914”(association)	0.640
RNASEH2C	RNASEH2A	psi-mi:“MI:0914”(association)	0.640
AGPAT1	RNASEH2A	psi-mi:“MI:0915”(physical association)	0.590
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
KPTN	EIF4G3	psi-mi:“MI:0914”(association)	0.530
FAM136A	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
RNASEH2B	SAP18	psi-mi:“MI:0914”(association)	0.350
RNASEH2A	PHF20L1	psi-mi:“MI:0914”(association)	0.350
C6orf141	KRBA1	psi-mi:“MI:0914”(association)	0.350
RIN3		psi-mi:“MI:0914”(association)	0.350
HTRA2	VWA8	psi-mi:“MI:0914”(association)	0.350
IMMP1L	EIF1AY	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
MAST1	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
DNAJA1	HSPA8	psi-mi:“MI:0914”(association)	0.350
DNAJA2	TUBA1B	psi-mi:“MI:0914”(association)	0.350
RNASEH2A	NDUFA3	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
NUBP2	POTEF	psi-mi:“MI:0914”(association)	0.350
KLHL1	SNX2	psi-mi:“MI:0914”(association)	0.350
NOX5	RNASEH2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (104): RNASEH2A (Affinity Capture-RNA), RNASEH2A (Affinity Capture-RNA), RNASEH2A (Affinity Capture-MS), RNASEH2A (Affinity Capture-MS), RNASEH2A (Affinity Capture-MS), RNASEH2A (Affinity Capture-MS), RNASEH2A (Affinity Capture-MS), RNASEH2A (Affinity Capture-MS), EDF1 (Co-fractionation), RNASEH2A (Co-fractionation), RNASEH2A (Co-fractionation), SETD3 (Co-fractionation), RNASEH2A (Proximity Label-MS), DMXL1 (Affinity Capture-MS), INPP5B (Affinity Capture-MS)

ESM2 similar proteins: A2VD33, A5PK19, A6QPU5, O75792, O95352, P11172, P13439, P31754, P41111, Q02053, Q0ZHH6, Q14181, Q16798, Q2TBT5, Q32PX9, Q3MHH4, Q3TX08, Q3V384, Q5EBA1, Q5R514, Q5R7A2, Q5RF36, Q5U209, Q641W2, Q641Y5, Q6DD88, Q6IQS6, Q80YD1, Q86SQ9, Q8BIP0, Q8BMF3, Q8BML9, Q8N6R0, Q8WV93, Q91YH5, Q91YR5, Q921Q3, Q96T60, Q9BT22, Q9CWY8

Diamond homologs: A0B796, A0L4Z0, A0Q7F9, A0RV25, A1RU36, A1RYM0, A2BL34, A2BT77, A2BYM8, A2STJ6, A3PEZ1, A4FWE5, A4IM80, A4IX19, A4SYT7, A4WHQ7, A4XLE8, A5ULV6, A5VNW6, A6UQ18, A6UUM1, A6VGW0, A6WW84, A7I9P7, A7NCM0, A8G702, A8MAH5, A9A9T9, A9M3R5, A9M8G2, B0CK74, B0R6T4, B0RW80, B0TYD6, B1XTV7, B1YB67, B2SGW7, B2UV86, B3CM59, B5Z8X1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RNASEH2A	“form complex”	“RNase H2 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

490 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	18
Uncertain significance	177
Likely benign	222
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1804035	NM_006397.3(RNASEH2A):c.859T>C (p.Tyr287His)	Pathogenic
2121714	NM_006397.3(RNASEH2A):c.447C>A (p.Tyr149Ter)	Pathogenic
2129412	NM_006397.3(RNASEH2A):c.263_267dup (p.Gly90fs)	Pathogenic
2837059	NM_006397.3(RNASEH2A):c.471dup (p.Pro158fs)	Pathogenic
2840647	NM_006397.3(RNASEH2A):c.223G>T (p.Glu75Ter)	Pathogenic
2862481	NM_006397.3(RNASEH2A):c.339_343dup (p.Ser115Ter)	Pathogenic
2879361	NM_006397.3(RNASEH2A):c.543_544del (p.Ala182fs)	Pathogenic
2905764	NM_006397.3(RNASEH2A):c.160del (p.Leu54fs)	Pathogenic
2977654	NM_006397.3(RNASEH2A):c.346del (p.Leu116fs)	Pathogenic
2982412	NM_006397.3(RNASEH2A):c.229del (p.Glu77fs)	Pathogenic
3248441	NC_000019.9:g.(?12920865)(12921238_?)del	Pathogenic
3669468	NM_006397.3(RNASEH2A):c.447C>G (p.Tyr149Ter)	Pathogenic
3703598	NM_006397.3(RNASEH2A):c.205_208del (p.Lys69fs)	Pathogenic
4711504	NM_006397.3(RNASEH2A):c.238_241del (p.Phe80fs)	Pathogenic
4717679	NM_006397.3(RNASEH2A):c.403_406dup (p.Thr136fs)	Pathogenic
636354	NM_006397.3(RNASEH2A):c.589del (p.Glu197fs)	Pathogenic
66065	NM_006397.3(RNASEH2A):c.75C>T (p.Arg25=)	Pathogenic
1066086	NM_006397.3(RNASEH2A):c.323+1G>T	Likely pathogenic
1468560	NM_006397.3(RNASEH2A):c.323+1G>A	Likely pathogenic
1488239	NM_006397.3(RNASEH2A):c.638-2A>G	Likely pathogenic
1687209	NM_006397.3(RNASEH2A):c.717del (p.Thr240fs)	Likely pathogenic
2202408	NM_006397.3(RNASEH2A):c.199+1G>C	Likely pathogenic
2498381	NM_006397.3(RNASEH2A):c.549+1G>T	Likely pathogenic
2722788	NM_006397.3(RNASEH2A):c.200-1G>T	Likely pathogenic
2769892	NM_006397.3(RNASEH2A):c.549+1G>A	Likely pathogenic
3034099	NM_006397.3(RNASEH2A):c.718_719delinsGCAT (p.Thr240fs)	Likely pathogenic
3067855	NM_006397.3(RNASEH2A):c.704G>C (p.Arg235Pro)	Likely pathogenic
3583480	NM_006397.3(RNASEH2A):c.543T>A (p.Cys181Ter)	Likely pathogenic
3583481	NM_006397.3(RNASEH2A):c.669_670del (p.Val224fs)	Likely pathogenic
3583482	NM_006397.3(RNASEH2A):c.762-2A>G	Likely pathogenic

SpliceAI

1015 predictions. Top by Δscore:

Variant	Effect	Δscore
19:12807078:AG:A	donor_loss	1.0000
19:12807079:GG:G	donor_loss	1.0000
19:12807080:GTGA:G	donor_loss	1.0000
19:12807081:T:A	donor_loss	1.0000
19:12807325:GGGCG:G	donor_gain	1.0000
19:12807326:GGCGG:G	donor_gain	1.0000
19:12807415:ACAG:A	acceptor_gain	1.0000
19:12807417:A:AG	acceptor_gain	1.0000
19:12807417:AG:A	acceptor_gain	1.0000
19:12807418:G:GG	acceptor_gain	1.0000
19:12807418:GG:G	acceptor_gain	1.0000
19:12810060:T:TA	acceptor_gain	1.0000
19:12810063:T:TA	acceptor_gain	1.0000
19:12810065:T:TA	acceptor_gain	1.0000
19:12810066:G:A	acceptor_gain	1.0000
19:12810067:GCAGG:G	acceptor_loss	1.0000
19:12810069:A:AG	acceptor_gain	1.0000
19:12810069:AG:A	acceptor_gain	1.0000
19:12810070:G:GA	acceptor_gain	1.0000
19:12810070:GG:G	acceptor_gain	1.0000
19:12810070:GGT:G	acceptor_gain	1.0000
19:12810070:GGTA:G	acceptor_gain	1.0000
19:12810205:CAAG:C	donor_loss	1.0000
19:12810206:AAGG:A	donor_loss	1.0000
19:12810207:AGGTC:A	donor_loss	1.0000
19:12810208:GGTC:G	donor_loss	1.0000
19:12810209:G:A	donor_loss	1.0000
19:12810209:G:GG	donor_gain	1.0000
19:12810311:CCACA:C	acceptor_loss	1.0000
19:12810312:CACA:C	acceptor_loss	1.0000

AlphaMissense

1936 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:12810194:A:C	S179R	0.998
19:12810196:C:A	S179R	0.998
19:12810196:C:G	S179R	0.998
19:12813157:T:A	W238R	0.997
19:12813157:T:C	W238R	0.997
19:12810150:T:A	V164D	0.996
19:12810208:G:C	K183N	0.996
19:12810208:G:T	K183N	0.996
19:12806800:G:C	G43R	0.995
19:12810204:C:A	A182D	0.995
19:12813159:G:C	W238C	0.995
19:12813159:G:T	W238C	0.995
19:12807213:G:C	K69N	0.994
19:12807213:G:T	K69N	0.994
19:12810192:C:A	A178D	0.994
19:12806788:G:C	G39R	0.993
19:12807008:G:A	G43D	0.993
19:12806786:G:T	R38M	0.992
19:12806787:G:C	R38S	0.992
19:12806787:G:T	R38S	0.992
19:12806789:G:A	G39D	0.992
19:12810189:C:A	A177D	0.992
19:12810324:G:C	R186P	0.992
19:12806783:G:A	G37D	0.991
19:12810081:A:T	D141V	0.991
19:12810082:C:A	D141E	0.991
19:12810082:C:G	D141E	0.991
19:12813146:T:A	V234D	0.991
19:12813151:T:C	F236L	0.991
19:12813153:C:A	F236L	0.991

dbSNP variants (sampled 300 via entrez): RS1000188582 (19:12805894 C>A), RS1000282096 (19:12804738 A>G), RS1000346872 (19:12804956 A>C,G), RS1000359807 (19:12810321 C>T), RS1000964856 (19:12809101 G>A), RS1001313810 (19:12808826 G>A), RS1001936952 (19:12804616 C>A), RS1002140099 (19:12813503 C>G), RS1002295115 (19:12814047 TTTTAA>T), RS1002369514 (19:12804888 C>A,G,T), RS1002475598 (19:12812714 A>G), RS1002683325 (19:12808568 C>T), RS1002780613 (19:12812515 G>A,C), RS1003496664 (19:12811433 G>A), RS1003705249 (19:12812948 T>A)

Disease associations

OMIM: gene MIM:606034 | disease phenotypes: MIM:610333, MIM:225750

GenCC curated gene-disease

Disease	Classification	Inheritance
Aicardi-Goutieres syndrome 4	Definitive	Autosomal recessive
Aicardi-Goutieres syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
RNASEH2A-related type 1 interferonopathy	Definitive	AR

Mondo (3): Aicardi-Goutieres syndrome 4 (MONDO:0012472), Aicardi-Goutieres syndrome (MONDO:0018866), RNASEH2A-related type 1 interferonopathy (MONDO:0700259)

Orphanet (1): Aicardi-Goutières syndrome (Orphanet:51)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000625	Eyelid coloboma
HP:0000639	Nystagmus
HP:0000737	Irritability
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000958	Dry skin
HP:0000965	Cutis marmorata
HP:0001063	Acrocyanosis
HP:0001087	Developmental glaucoma
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001357	Plagiocephaly
HP:0001369	Arthritis
HP:0001433	Hepatosplenomegaly

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003830_20	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	2.000000e-07
GCST003830_6	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	1.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C563681	Aicardi-Goutieres Syndrome 4 (supp.)
C535607	Aicardi-Goutieres syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects expression, decreases expression, increases expression	4
Benzo(a)pyrene	affects methylation, increases expression	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
cobaltous chloride	decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Mercury	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	affects cotreatment, decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
jinfukang	increases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3G2	Abcam HEK293T RNASEH2A KO	Transformed cell line	Female

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02363452	PHASE2	COMPLETED	Reverse Transcriptase Inhibitors in AGS
NCT03921554	PHASE2	COMPLETED	JAK Inhibitor Treatment in AGS
NCT04731103	PHASE2	COMPLETED	Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome
NCT05613868	PHASE2	TERMINATED	TPN-101 in Aicardi-Goutières Syndrome (AGS)
NCT04517253	PHASE2/PHASE3	TERMINATED	A Study of Baricitinib (LY3009104) in Adult and Pediatric Japanese Participants With NNS/CANDLE, SAVI, and AGS
NCT03304717	PHASE1/PHASE2	WITHDRAWN	Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
NCT01724580	Not specified	APPROVED_FOR_MARKETING	Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT06898372	Not specified	COMPLETED	Evaluate the Efficacy of Anti-Jak1 Inhibitors as Treatment for Patients With Aicardi-Goutières Syndrome