Aicardi-Goutieres syndrome 4

Summary

Aicardi-Goutieres syndrome 4 (MONDO:0012472) is a disease caused by RNASEH2A (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RNASEH2A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 515

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Aicardi-Goutieres syndrome 4
Mondo ID	MONDO:0012472
MeSH	C563681
OMIM	610333
UMLS	C1835912
MedGen	332084
GARD	0015480
Is cancer (heuristic)	no

Also known as: AGS4 · Aicardi-Goutieres syndrome 4 · Aicardi-Goutieres syndrome caused by mutation in RNASEH2A · Aicardi-Goutieres syndrome type 4 · RNASEH2A Aicardi-Goutieres syndrome · RNASEH2A-related Aicardi-Goutieres syndrome

Data availability: 515 ClinVar variants · 3 GenCC gene-disease records.

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 4

Related subtypes (9): basal ganglia calcification, idiopathic, childhood-onset, Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome 2, Aicardi-Goutieres syndrome 3, 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

515 retrieved; paginated sample, class counts are floors:

248 likely benign, 188 uncertain significance, 21 pathogenic, 17 conflicting classifications of pathogenicity, 17 likely pathogenic, 11 benign, 5 pathogenic/likely pathogenic, 5 benign/likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2786566	NM_006397.3(RNASEH2A):c.13G>T (p.Glu5Ter)	LOC117038795	Pathogenic	criteria provided, single submitter
2878648	NM_006397.3(RNASEH2A):c.87C>A (p.Cys29Ter)	LOC117038795	Pathogenic	criteria provided, single submitter
4641	NM_006397.3(RNASEH2A):c.109G>A (p.Gly37Ser)	LOC117038795	Pathogenic	no assertion criteria provided
66067	NM_006397.3(RNASEH2A):c.69G>A (p.Val23=)	LOC117038795	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1204332	NM_006397.3(RNASEH2A):c.657G>A (p.Trp219Ter)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804035	NM_006397.3(RNASEH2A):c.859T>C (p.Tyr287His)	RNASEH2A	Pathogenic	criteria provided, single submitter
2121714	NM_006397.3(RNASEH2A):c.447C>A (p.Tyr149Ter)	RNASEH2A	Pathogenic	criteria provided, single submitter
2129412	NM_006397.3(RNASEH2A):c.263_267dup (p.Gly90fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
2837059	NM_006397.3(RNASEH2A):c.471dup (p.Pro158fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
2840647	NM_006397.3(RNASEH2A):c.223G>T (p.Glu75Ter)	RNASEH2A	Pathogenic	criteria provided, single submitter
2862481	NM_006397.3(RNASEH2A):c.339_343dup (p.Ser115Ter)	RNASEH2A	Pathogenic	criteria provided, single submitter
2879361	NM_006397.3(RNASEH2A):c.543_544del (p.Ala182fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
2905764	NM_006397.3(RNASEH2A):c.160del (p.Leu54fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
2977654	NM_006397.3(RNASEH2A):c.346del (p.Leu116fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
2982412	NM_006397.3(RNASEH2A):c.229del (p.Glu77fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
3248441	NC_000019.9:g.(?12920865)(12921238_?)del	RNASEH2A	Pathogenic	criteria provided, single submitter
3669468	NM_006397.3(RNASEH2A):c.447C>G (p.Tyr149Ter)	RNASEH2A	Pathogenic	criteria provided, single submitter
3703598	NM_006397.3(RNASEH2A):c.205_208del (p.Lys69fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
445579	NM_006397.3(RNASEH2A):c.557G>A (p.Arg186Gln)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4711504	NM_006397.3(RNASEH2A):c.238_241del (p.Phe80fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
4717679	NM_006397.3(RNASEH2A):c.403_406dup (p.Thr136fs)	RNASEH2A	Pathogenic	criteria provided, single submitter
632305	NM_006397.3(RNASEH2A):c.206dup (p.Thr70fs)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636354	NM_006397.3(RNASEH2A):c.589del (p.Glu197fs)	RNASEH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
66065	NM_006397.3(RNASEH2A):c.75C>T (p.Arg25=)	RNASEH2A	Pathogenic	no assertion criteria provided
66068	NM_006397.3(RNASEH2A):c.556C>T (p.Arg186Trp)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457169	NC_000019.9:g.(?12757434)(13617038_?)del	WDR83OS	Pathogenic	criteria provided, single submitter
2138239	NM_006397.3(RNASEH2A):c.127+1G>C	LOC117038795	Likely pathogenic	criteria provided, single submitter
1066086	NM_006397.3(RNASEH2A):c.323+1G>T	RNASEH2A	Likely pathogenic	criteria provided, single submitter
1468560	NM_006397.3(RNASEH2A):c.323+1G>A	RNASEH2A	Likely pathogenic	criteria provided, single submitter
1488239	NM_006397.3(RNASEH2A):c.638-2A>G	RNASEH2A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
RNASEH2A	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASEH2A	Orphanet:51	Aicardi-Goutières syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEH2A	HGNC:18518	ENSG00000104889	O75792	Ribonuclease H2 subunit A	gencc,clinvar
DNASE2	HGNC:2960	ENSG00000105612	O00115	Deoxyribonuclease-2-alpha	clinvar
WDR83OS	HGNC:30203	ENSG00000105583	Q9Y284	PAT complex subunit Asterix	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASEH2A	Ribonuclease H2 subunit A	Catalytic subunit of RNase HII, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
DNASE2	Deoxyribonuclease-2-alpha	Hydrolyzes DNA under acidic conditions with a preference for double-stranded DNA.
WDR83OS	PAT complex subunit Asterix	Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEH2A	Enzyme (other)	yes	3.1.26.4	RNase_HII/HIII, RNase_H2_suA, RNaseH-like_sf
DNASE2	Enzyme (other)	yes	3.1.22.1	DNase_II
WDR83OS	Other/Unknown	no		ASTER

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
ganglionic eminence	1
ventricular zone	1
lateral globus pallidus	1
pancreatic ductal cell	1
stromal cell of endometrium	1
fallopian tube	1
pituitary gland	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEH2A	140	ubiquitous	marker	ganglionic eminence, embryo, ventricular zone
DNASE2	256	ubiquitous	marker	pancreatic ductal cell, stromal cell of endometrium, lateral globus pallidus
WDR83OS	134	ubiquitous	marker	right adrenal gland, pituitary gland, fallopian tube

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNASEH2A	3,129
WDR83OS	979
DNASE2	709

Intra-cohort edges

A	B	Sources
DNASE2	RNASEH2A	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNASEH2A	O75792	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNASE2	O00115	91.52
WDR83OS	Q9Y284	62.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lysosome Vesicle Biogenesis	1	326.3×	0.003	DNASE2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication, removal of RNA primer	1	1404.3×	0.005	RNASEH2A
enucleate erythrocyte differentiation	1	702.2×	0.005	DNASE2
multi-pass transmembrane protein insertion into ER membrane	1	624.1×	0.005	WDR83OS
protein insertion into ER membrane	1	510.7×	0.005	WDR83OS
apoptotic DNA fragmentation	1	401.2×	0.005	DNASE2
DNA metabolic process	1	351.1×	0.005	DNASE2
mismatch repair	1	216.1×	0.007	RNASEH2A
regulation of immune response	1	165.2×	0.007	DNASE2
RNA catabolic process	1	151.8×	0.007	RNASEH2A
DNA replication	1	55.1×	0.018	RNASEH2A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNASEH2A	0	0
DNASE2	0	0
WDR83OS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DNASE2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASEH2A	3.1.26.4	ribonuclease H
DNASE2	3.1.22.1	deoxyribonuclease II

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	RNASEH2A
D	Druggable family + AlphaFold only, no drug	1	DNASE2
E	Difficult family or no structure, no drug	1	WDR83OS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNASEH2A	0	—
DNASE2	1	—
WDR83OS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.