Aicardi-Goutieres syndrome 5

Summary

Aicardi-Goutieres syndrome 5 (MONDO:0013059) is a disease caused by SAMHD1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SAMHD1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 910

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Aicardi-Goutieres syndrome 5
Mondo ID	MONDO:0013059
MeSH	C535608
OMIM	612952
NCIT	C168564
UMLS	C2749659
MedGen	413116
GARD	0010151
Is cancer (heuristic)	no

Also known as: AGS5 · Aicardi-Goutieres syndrome 5 · Aicardi-Goutieres syndrome caused by mutation in SAMHD1 · Aicardi-Goutieres syndrome type 5 · SAMHD1 Aicardi-Goutieres syndrome · SAMHD1-related Aicardi-Goutieres syndrome

Data availability: 910 ClinVar variants · 5 GenCC gene-disease records · 9 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 5

Related subtypes (9): basal ganglia calcification, idiopathic, childhood-onset, Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome 2, Aicardi-Goutieres syndrome 3, Aicardi-Goutieres syndrome 4, 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

600 retrieved; paginated sample, class counts are floors:

301 likely benign, 201 uncertain significance, 52 pathogenic, 22 likely pathogenic, 9 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 5 benign, 3 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
126402	NC_000020.11:g.(36898545_36904156)(36951644?)del	LOC130065805	Pathogenic	no assertion criteria provided
1032693	NM_015474.4(SAMHD1):c.1609-1G>T	SAMHD1	Pathogenic	criteria provided, single submitter
1069266	NM_015474.4(SAMHD1):c.1419del (p.Asp472_Tyr473insTer)	SAMHD1	Pathogenic	criteria provided, single submitter
1070389	NC_000020.10:g.(?35563422)(35563602_?)del	SAMHD1	Pathogenic	criteria provided, single submitter
1071265	NM_015474.4(SAMHD1):c.1334dup (p.Leu445fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1071571	NM_015474.4(SAMHD1):c.1567A>T (p.Lys523Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
1072306	NM_015474.4(SAMHD1):c.568_577del (p.Gln190fs)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074516	NM_015474.4(SAMHD1):c.328del (p.Ile110fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1076058	NM_015474.4(SAMHD1):c.68C>G (p.Ser23Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076079	NM_015474.4(SAMHD1):c.1321dup (p.Ala441fs)	SAMHD1	Pathogenic	criteria provided, single submitter
126403	Single allele	SAMHD1	Pathogenic	no assertion criteria provided
126406	NM_015474.4(SAMHD1):c.1324C>T (p.Arg442Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
126407	NM_015474.4(SAMHD1):c.1411-2A>G	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
126411	NM_015474.4(SAMHD1):c.428G>A (p.Arg143His)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126413	NM_015474.4(SAMHD1):c.649_650insG (p.Phe217fs)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1359912	NM_015474.4(SAMHD1):c.460del (p.Tyr154fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1384819	NM_015474.4(SAMHD1):c.316C>T (p.Arg106Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399339	NM_015474.4(SAMHD1):c.196A>T (p.Lys66Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
1410719	NM_015474.4(SAMHD1):c.638_647del (p.Phe213fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1411720	NM_015474.4(SAMHD1):c.1123C>T (p.Gln375Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
1411961	NC_000020.10:g.(?35563412)(35569534_?)del	SAMHD1	Pathogenic	criteria provided, single submitter
1417058	NM_015474.4(SAMHD1):c.181G>T (p.Glu61Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
1453299	NM_015474.4(SAMHD1):c.693G>A (p.Trp231Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453548	NM_015474.4(SAMHD1):c.703C>T (p.Gln235Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453957	NC_000020.10:g.(?35575121)(35580046_?)del	SAMHD1	Pathogenic	criteria provided, single submitter
1454961	NM_015474.4(SAMHD1):c.1584del (p.Ala529fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455178	NM_015474.4(SAMHD1):c.127A>T (p.Lys43Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
1455349	NM_015474.4(SAMHD1):c.101dup (p.Leu36fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1455381	NM_015474.4(SAMHD1):c.1444_1453del (p.Ser482fs)	SAMHD1	Pathogenic	criteria provided, single submitter
1456508	NC_000020.10:g.(?35521335)(35580046_?)del	SAMHD1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
SAMHD1	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 5	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	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
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	gencc,clinvar
CTNNBL1	HGNC:15879	ENSG00000132792	Q8WYA6	Beta-catenin-like protein 1	clinvar
TLDC2	HGNC:16112	ENSG00000101342	A0PJX2	TLD domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
CTNNBL1	Beta-catenin-like protein 1	Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing.
TLDC2	TLD domain-containing protein 2	Inhibits the activity of the vacuolar-type ATPase (V-ATPase) by inducing disassembly of the V-ATPase complex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
CTNNBL1	Other/Unknown	no		ARM-like, CTNNBL1_N, ARM-type_fold
TLDC2	Other/Unknown	no		TLDc_dom

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
monocyte	1
mononuclear cell	1
pericardium	1
left testis	1
right testis	1
spleen	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
CTNNBL1	280	ubiquitous	marker	left testis, right testis, spleen
TLDC2	160	tissue_specific	marker	sural nerve, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTNNBL1	2,346
SAMHD1	2,186
TLDC2	254

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMHD1	Q9Y3Z3	76
CTNNBL1	Q8WYA6	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLDC2	A0PJX2	85.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 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
Nucleotide catabolism	1	634.4×	0.014	SAMHD1
Metabolism of nucleotides	1	150.3×	0.030	SAMHD1
Interferon alpha/beta signaling	1	76.1×	0.037	SAMHD1
Interferon Signaling	1	60.1×	0.037	SAMHD1
mRNA Splicing - Major Pathway	1	27.3×	0.062	CTNNBL1
Dengue Virus-Host Interactions	1	22.8×	0.062	CTNNBL1
Cytokine Signaling in Immune system	1	20.4×	0.062	SAMHD1
Immune System	1	6.5×	0.165	SAMHD1
Metabolism	1	5.8×	0.165	SAMHD1

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
dGTP catabolic process	1	2808.7×	0.002	SAMHD1
deoxyribonucleotide catabolic process	1	2808.7×	0.002	SAMHD1
somatic diversification of immunoglobulins	1	2808.7×	0.002	CTNNBL1
dATP catabolic process	1	2808.7×	0.002	SAMHD1
DNA strand resection involved in replication fork processing	1	702.2×	0.005	SAMHD1
somatic hypermutation of immunoglobulin genes	1	351.1×	0.009	SAMHD1
negative regulation of type I interferon-mediated signaling pathway	1	255.3×	0.010	SAMHD1
regulation of innate immune response	1	216.1×	0.010	SAMHD1
protein homotetramerization	1	79.1×	0.025	SAMHD1
double-strand break repair via homologous recombination	1	52.0×	0.034	SAMHD1
response to oxidative stress	1	43.5×	0.037	TLDC2
mRNA splicing, via spliceosome	1	30.5×	0.049	CTNNBL1
adaptive immune response	1	28.1×	0.049	CTNNBL1
defense response to virus	1	23.1×	0.055	SAMHD1
positive regulation of apoptotic process	1	18.9×	0.062	CTNNBL1
DNA damage response	1	17.8×	0.062	SAMHD1
immune response	1	15.7×	0.066	SAMHD1
innate immune response	1	11.2×	0.087	SAMHD1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SAMHD1	0	0
CTNNBL1	0	0
TLDC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SAMHD1	4	Binding:3, Functional:1
CTNNBL1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SAMHD1	3.1.5.B1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SAMHD1, CTNNBL1, TLDC2

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)
SAMHD1	4	—
CTNNBL1	1	—
TLDC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.