Aicardi-Goutieres syndrome 2

Summary

Aicardi-Goutieres syndrome 2 (MONDO:0012429) is a disease caused by RNASEH2B (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: RNASEH2B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 490

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Aicardi-Goutieres syndrome 2
Mondo ID	MONDO:0012429
OMIM	610181
NCIT	C165673
UMLS	C3489724
MedGen	483677
GARD	0015472
Is cancer (heuristic)	no

Also known as: AGS2 · Aicardi-Goutieres syndrome 2 · Aicardi-Goutieres syndrome caused by mutation in RNASEH2B · Aicardi-Goutieres syndrome type 2 · RNASEH2B Aicardi-Goutieres syndrome · RNASEH2B-related Aicardi-Goutieres syndrome

Data availability: 490 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › Aicardi-Goutieres syndrome › Aicardi-Goutieres syndrome 2

Related subtypes (9): basal ganglia calcification, idiopathic, childhood-onset, Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome 3, Aicardi-Goutieres syndrome 4, Aicardi-Goutieres syndrome 5, Aicardi-Goutieres syndrome 6, Aicardi-Goutieres syndrome 7, Aicardi-Goutieres syndrome 8, Aicardi-Goutieres syndrome 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

490 retrieved; paginated sample, class counts are floors:

234 likely benign, 172 uncertain significance, 26 pathogenic, 17 likely pathogenic, 16 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 9 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2708280	NM_024570.4(RNASEH2B):c.47_48dup (p.Val17fs)	LOC130009810	Pathogenic	criteria provided, single submitter
1071567	NM_024570.4(RNASEH2B):c.132T>A (p.Cys44Ter)	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1262	NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1263	NM_024570.4(RNASEH2B):c.554T>G (p.Val185Gly)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353481	NM_024570.4(RNASEH2B):c.129dup (p.Cys44fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
1399926	NM_024570.4(RNASEH2B):c.172C>T (p.Gln58Ter)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451439	NM_024570.4(RNASEH2B):c.4del (p.Ala2fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
1451862	NM_024570.4(RNASEH2B):c.476del (p.Ser159fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
1456507	NM_024570.4(RNASEH2B):c.331C>T (p.Gln111Ter)	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
191042	NM_024570.4(RNASEH2B):c.356A>G (p.Asp119Gly)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426831	NC_000013.10:g.(?51484213)(51484296_?)del	RNASEH2B	Pathogenic	criteria provided, single submitter
2426832	NC_000013.10:g.(?51501523)(51530610_?)del	RNASEH2B	Pathogenic	criteria provided, single submitter
2764119	NM_024570.4(RNASEH2B):c.648del (p.Ser217fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
2820897	NM_024570.4(RNASEH2B):c.509dup (p.Val171fs)	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2842511	NM_024570.4(RNASEH2B):c.69T>A (p.Tyr23Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
2859739	NM_024570.4(RNASEH2B):c.83C>G (p.Ser28Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
2902183	NM_024570.4(RNASEH2B):c.511-1G>A	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244196	NC_000013.10:g.(?51484213)(51530610_?)del	RNASEH2B	Pathogenic	criteria provided, single submitter
3244197	NC_000013.10:g.(?51484213)(51528141_?)del	RNASEH2B	Pathogenic	criteria provided, single submitter
3244198	NC_000013.10:g.(?51503591)(51530610_?)del	RNASEH2B	Pathogenic	criteria provided, single submitter
3576270	NM_024570.4(RNASEH2B):c.468C>G (p.Tyr156Ter)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3720083	NM_024570.4(RNASEH2B):c.98dup (p.Asn33fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
3769137	NC_000013.10:g.(?51483926)(51484277_51501542)del	RNASEH2B	Pathogenic	criteria provided, single submitter
424112	NM_024570.4(RNASEH2B):c.437-1G>A	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4687841	NM_024570.4(RNASEH2B):c.281dup (p.Phe95fs)	RNASEH2B	Pathogenic	criteria provided, single submitter
4727551	NM_024570.4(RNASEH2B):c.693C>G (p.Tyr231Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
4735463	NM_024570.4(RNASEH2B):c.737C>G (p.Ser246Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
540251	NM_024570.4(RNASEH2B):c.667G>T (p.Glu223Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
566198	NM_024570.4(RNASEH2B):c.136+1del	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
567225	NM_024570.4(RNASEH2B):c.121del (p.Val41fs)	RNASEH2B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RNASEH2B	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASEH2B	Orphanet:51	Aicardi-Goutières syndrome
RNASEH2B	Orphanet:689234	RNASEH2B-related hereditary spastic paraplegia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEH2B	HGNC:25671	ENSG00000136104	Q5TBB1	Ribonuclease H2 subunit B	gencc,clinvar
RNASEH2B-AS1	HGNC:39967	ENSG00000233672		RNASEH2B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASEH2B	Ribonuclease H2 subunit B	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEH2B	Enzyme (other)	yes	3.1.26.4	RNase_H2_suB_wHTH, RNase_H2_suB, Rnh202_N
RNASEH2B-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEH2B	242	ubiquitous	marker	calcaneal tendon, ganglionic eminence, ventricular zone
RNASEH2B-AS1	132	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNASEH2B	1,306
RNASEH2B-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNASEH2B	Q5TBB1	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ribonucleotide metabolic process	1	16852.0×	6e-04	RNASEH2B
regulation of G2/M transition of mitotic cell cycle	1	1296.3×	0.003	RNASEH2B
regulation of DNA damage checkpoint	1	1123.5×	0.003	RNASEH2B
mismatch repair	1	648.1×	0.004	RNASEH2B
RNA catabolic process	1	455.5×	0.004	RNASEH2B
fibroblast proliferation	1	391.9×	0.004	RNASEH2B
positive regulation of fibroblast proliferation	1	295.6×	0.005	RNASEH2B
gene expression	1	79.9×	0.014	RNASEH2B
in utero embryonic development	1	72.0×	0.014	RNASEH2B
negative regulation of gene expression	1	69.1×	0.014	RNASEH2B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNASEH2B	0	0
RNASEH2B-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASEH2B	3.1.26.4	ribonuclease H

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RNASEH2B
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RNASEH2B-AS1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RNASEH2B	0	—
RNASEH2B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.