Aicardi-Goutieres syndrome 3

Summary

Aicardi-Goutieres syndrome 3 (MONDO:0012471) is a disease caused by RNASEH2C (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: RNASEH2C (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 370

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Aicardi-Goutieres syndrome 3
Mondo ID	MONDO:0012471
MeSH	C563683
OMIM	610329
UMLS	C1835916
MedGen	324389
GARD	0015479
Is cancer (heuristic)	no

Also known as: AGS3 · Aicardi-Goutieres syndrome 3 · Aicardi-Goutieres syndrome caused by mutation in RNASEH2C · Aicardi-Goutieres syndrome type 3 · RNASEH2C -related Aicardi-Goutieres syndrome · RNASEH2C Aicardi-Goutieres syndrome

Data availability: 370 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 3

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

370 retrieved; paginated sample, class counts are floors:

177 likely benign, 163 uncertain significance, 11 conflicting classifications of pathogenicity, 10 benign, 6 benign/likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1260	NM_032193.4(RNASEH2C):c.205C>T (p.Arg69Trp)	RNASEH2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299509	NM_032193.4(RNASEH2C):c.412C>T (p.Pro138Ser)	RNASEH2C	Likely pathogenic	criteria provided, single submitter
983437	NM_032193.4(RNASEH2C):c.450G>T (p.Trp150Cys)	RNASEH2C	Likely pathogenic	criteria provided, single submitter
305343	NM_032193.4(RNASEH2C):c.*719T>G	KAT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1128250	NM_032193.4(RNASEH2C):c.469-7G>T	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203392	NM_032193.4(RNASEH2C):c.178dup (p.Glu60fs)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2171931	NM_032193.4(RNASEH2C):c.194G>A (p.Gly65Asp)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2896167	NM_032193.4(RNASEH2C):c.340C>A (p.Arg114=)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305359	NM_032193.4(RNASEH2C):c.468+8G>A	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305361	NM_032193.4(RNASEH2C):c.417C>G (p.Gly139=)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305366	NM_032193.4(RNASEH2C):c.173-14G>A	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419543	NM_032193.4(RNASEH2C):c.451C>T (p.Pro151Ser)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636680	NM_032193.4(RNASEH2C):c.247G>A (p.Val83Met)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806694	NM_032193.4(RNASEH2C):c.227C>T (p.Pro76Leu)	RNASEH2C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424770	NC_000011.9:g.(?64973914)(70052579_?)dup	ACTN3	Uncertain significance	criteria provided, single submitter
2426697	NC_000011.9:g.(?65325080)(65639825_?)del	AP5B1	Uncertain significance	criteria provided, single submitter
305323	NM_032193.4(RNASEH2C):c.*1977C>T	KAT5	Uncertain significance	criteria provided, single submitter
305325	NM_032193.4(RNASEH2C):c.*1831G>A	KAT5	Uncertain significance	criteria provided, single submitter
305326	NM_032193.4(RNASEH2C):c.*1806G>A	KAT5	Uncertain significance	criteria provided, single submitter
305327	NM_032193.4(RNASEH2C):c.*1778C>G	KAT5	Uncertain significance	criteria provided, single submitter
305329	NM_032193.4(RNASEH2C):c.*1768C>T	KAT5	Uncertain significance	criteria provided, single submitter
305330	NM_032193.4(RNASEH2C):c.*1737C>T	KAT5	Uncertain significance	criteria provided, single submitter
305331	NM_032193.4(RNASEH2C):c.*1658G>C	KAT5	Uncertain significance	criteria provided, single submitter
305333	NM_032193.4(RNASEH2C):c.*1594G>A	KAT5	Uncertain significance	criteria provided, single submitter
305335	NM_032193.4(RNASEH2C):c.*1504G>A	KAT5	Uncertain significance	criteria provided, single submitter
305337	NM_032193.4(RNASEH2C):c.*1217G>C	KAT5	Uncertain significance	criteria provided, single submitter
305340	NM_032193.4(RNASEH2C):c.*940A>G	KAT5	Uncertain significance	criteria provided, single submitter
305341	NM_032193.4(RNASEH2C):c.*862A>C	KAT5	Uncertain significance	criteria provided, single submitter
305342	NM_032193.4(RNASEH2C):c.*747G>A	KAT5	Uncertain significance	criteria provided, single submitter
305344	NM_032193.4(RNASEH2C):c.*706T>A	KAT5	Uncertain significance	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
RNASEH2C	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASEH2C	Orphanet:51	Aicardi-Goutières syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEH2C	HGNC:24116	ENSG00000172922	Q8TDP1	Ribonuclease H2 subunit C	gencc,clinvar
ACTN3	HGNC:165	ENSG00000248746	Q08043	Alpha-actinin-3	clinvar
AP5B1	HGNC:25104	ENSG00000254470	Q2VPB7	AP-5 complex subunit beta-1	clinvar
KAT5	HGNC:5275	ENSG00000172977	Q92993	Histone acetyltransferase KAT5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASEH2C	Ribonuclease H2 subunit C	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
ACTN3	Alpha-actinin-3	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
AP5B1	AP-5 complex subunit beta-1	As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.
KAT5	Histone acetyltransferase KAT5	Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEH2C	Enzyme (other)	yes	3.1.26.4	RNase_H2_suC, RNase_H2_subunit_C
ACTN3	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
AP5B1	Other/Unknown	no		AP5B1, AP5B1_N, AP5B1_middle
KAT5	Enzyme (other)	yes	2.3.1.48	Chromo/chromo_shadow_dom, HAT_MYST-type, Acyl_CoA_acyltransferase

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
pancreatic ductal cell	1
tendon of biceps brachii	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
bone marrow cell	1
leukocyte	1
monocyte	1
body of uterus	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEH2C	259	ubiquitous	marker	pancreatic ductal cell, tendon of biceps brachii, apex of heart
ACTN3	146	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, diaphragm
AP5B1	178	ubiquitous	yes	monocyte, leukocyte, bone marrow cell
KAT5	281	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KAT5	4,833
ACTN3	1,772
AP5B1	1,170
RNASEH2C	806

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNASEH2C	Q8TDP1	3
ACTN3	Q08043	3
KAT5	Q92993	3
AP5B1	Q2VPB7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensing of DNA Double Strand Breaks	1	951.7×	0.018	KAT5
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	475.8×	0.018	KAT5
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.018	KAT5
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.018	KAT5
Resolution of D-Loop Structures	1	317.2×	0.018	KAT5
Diseases of DNA repair	1	285.5×	0.018	KAT5
Nephrin family interactions	1	237.9×	0.018	ACTN3
DNA Double Strand Break Response	1	237.9×	0.018	KAT5
Impaired BRCA2 binding to PALB2	1	228.4×	0.018	KAT5
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	211.5×	0.018	KAT5
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	211.5×	0.018	KAT5
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	211.5×	0.018	KAT5
Cardiogenesis	1	211.5×	0.018	KAT5
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.018	KAT5
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.018	KAT5
Striated Muscle Contraction	1	154.3×	0.018	ACTN3
Homology Directed Repair	1	154.3×	0.018	KAT5
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.018	KAT5
Impaired BRCA2 binding to RAD51	1	154.3×	0.018	KAT5
Resolution of D-loop Structures through Holliday Junction Intermediates	1	150.3×	0.018	KAT5
HDR through Single Strand Annealing (SSA)	1	146.4×	0.018	KAT5
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.019	KAT5
DNA Double-Strand Break Repair	1	124.1×	0.020	KAT5
HDR through Homologous Recombination (HRR)	1	95.2×	0.024	KAT5
Nonhomologous End-Joining (NHEJ)	1	84.0×	0.026	KAT5
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.026	KAT5
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.026	KAT5
Cell-Cell communication	1	68.8×	0.026	ACTN3
Cellular Senescence	1	68.8×	0.026	KAT5
G2/M Checkpoints	1	67.2×	0.026	KAT5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of glucose catabolic process to lactate via pyruvate	1	4213.0×	0.007	ACTN3
positive regulation of fast-twitch skeletal muscle fiber contraction	1	2106.5×	0.007	ACTN3
regulation of the force of skeletal muscle contraction	1	1404.3×	0.007	ACTN3
positive regulation of mitotic sister chromatid segregation	1	1404.3×	0.007	KAT5
positive regulation of bone mineralization involved in bone maturation	1	1404.3×	0.007	ACTN3
peptidyl-lysine acetylation	1	1053.2×	0.007	KAT5
negative regulation of relaxation of muscle	1	1053.2×	0.007	ACTN3
positive regulation of protein acetylation	1	1053.2×	0.007	KAT5
skeletal muscle atrophy	1	842.6×	0.007	ACTN3
positive regulation of skeletal muscle tissue growth	1	842.6×	0.007	ACTN3
positive regulation of aggrephagy	1	702.2×	0.007	KAT5
transition between fast and slow fiber	1	601.9×	0.007	ACTN3
response to denervation involved in regulation of muscle adaptation	1	601.9×	0.007	ACTN3
negative regulation of oxidative phosphorylation	1	601.9×	0.007	ACTN3
lipid droplet disassembly	1	601.9×	0.007	KAT5
positive regulation of skeletal muscle fiber development	1	526.6×	0.007	ACTN3
positive regulation of attachment of mitotic spindle microtubules to kinetochore	1	526.6×	0.007	KAT5
regulation of aerobic respiration	1	526.6×	0.007	ACTN3
regulation of apoptotic process	2	41.7×	0.007	ACTN3, KAT5
regulation of hematopoietic stem cell differentiation	1	383.0×	0.009	KAT5
positive regulation of triglyceride biosynthetic process	1	324.1×	0.010	KAT5
positive regulation of circadian rhythm	1	300.9×	0.010	KAT5
negative regulation of glycolytic process	1	263.3×	0.011	ACTN3
positive regulation of regulatory T cell differentiation	1	234.1×	0.011	KAT5
muscle cell development	1	234.1×	0.011	ACTN3
negative regulation of calcineurin-NFAT signaling cascade	1	234.1×	0.011	ACTN3
sperm DNA condensation	1	221.7×	0.011	KAT5
DNA repair-dependent chromatin remodeling	1	168.5×	0.014	KAT5
mismatch repair	1	162.0×	0.014	RNASEH2C
negative regulation of double-strand break repair via homologous recombination	1	156.0×	0.014	KAT5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KAT5	2	3
RNASEH2C	0	0
ACTN3	0	0
AP5B1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COENZYME_A	3	KAT5
EPIGALOCATECHIN GALLATE	3	KAT5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KAT5	39	Binding:39

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASEH2C	3.1.26.4	ribonuclease H
KAT5	2.3.1.48	histone acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
COENZYME_A	3	KAT5
EPIGALOCATECHIN GALLATE	3	KAT5

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	1	KAT5
C	Druggable family + PDB, no drug	1	RNASEH2C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACTN3, AP5B1

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)
RNASEH2C	0	—
ACTN3	0	—
AP5B1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.