Singleton-Merten syndrome 1

Summary

Singleton-Merten syndrome 1 (MONDO:0024535) is a disease caused by IFIH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IFIH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1,527

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Singleton-Merten syndrome 1
Mondo ID	MONDO:0024535
OMIM	182250
UMLS	C4225427
MedGen	899946
GARD	0025417
Is cancer (heuristic)	no

Also known as: IFIH1 singleton-Merten dysplasia · SGMRT1 · singleton-Merten dysplasia caused by mutation in IFIH1

Data availability: 1,527 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary disorder of connective tissue › Singleton-Merten dysplasia › Singleton-Merten syndrome 1

Related subtypes (1): Singleton-Merten syndrome 2

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:

323 uncertain significance, 227 likely benign, 24 conflicting classifications of pathogenicity, 18 benign, 4 benign/likely benign, 2 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
137621	NM_022168.4(IFIH1):c.2159G>A (p.Arg720Gln)	IFIH1	Pathogenic	criteria provided, multiple submitters, no conflicts
137622	NM_022168.4(IFIH1):c.2336G>A (p.Arg779His)	IFIH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
137624	NM_022168.4(IFIH1):c.2335C>T (p.Arg779Cys)	IFIH1	Pathogenic	criteria provided, multiple submitters, no conflicts
189338	NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln)	IFIH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1000029	NM_022168.4(IFIH1):c.1609A>G (p.Lys537Glu)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001010	NM_022168.4(IFIH1):c.1134A>T (p.Gln378His)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001759	NM_022168.4(IFIH1):c.1765G>A (p.Ala589Thr)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009368	NM_022168.4(IFIH1):c.1152G>A (p.Trp384Ter)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034429	NM_022168.4(IFIH1):c.2182C>T (p.Arg728Ter)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038428	NM_022168.4(IFIH1):c.1590C>G (p.Asn530Lys)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042492	NM_022168.4(IFIH1):c.2305-2A>G	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054190	NM_022168.4(IFIH1):c.2317G>T (p.Glu773Ter)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054869	NM_022168.4(IFIH1):c.1784G>A (p.Arg595His)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058198	NM_022168.4(IFIH1):c.1498G>A (p.Ala500Thr)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1059157	NM_022168.4(IFIH1):c.1552A>G (p.Ile518Val)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1175189	NM_022168.4(IFIH1):c.1852C>T (p.Arg618Ter)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314738	NM_022168.4(IFIH1):c.2455-6T>A	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357956	NM_022168.4(IFIH1):c.767_769+2dup	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404014	NM_022168.4(IFIH1):c.2305-13A>G	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431399	NM_022168.4(IFIH1):c.1943del (p.Gly648fs)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432951	NM_022168.4(IFIH1):c.1658A>T (p.Lys553Ile)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472505	NM_022168.4(IFIH1):c.1960T>G (p.Cys654Gly)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1489881	NM_022168.4(IFIH1):c.1525C>T (p.Leu509=)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1492627	NM_022168.4(IFIH1):c.2573T>C (p.Ile858Thr)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1515590	NM_022168.4(IFIH1):c.442G>A (p.Asp148Asn)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1516067	NM_022168.4(IFIH1):c.453+1G>A	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1570850	NM_022168.4(IFIH1):c.1915G>A (p.Ala639Thr)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1638988	NM_022168.4(IFIH1):c.463G>A (p.Ala155Thr)	IFIH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000906	NM_022168.4(IFIH1):c.730T>C (p.Ser244Pro)	IFIH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001100	NM_022168.4(IFIH1):c.977T>C (p.Ile326Thr)	IFIH1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
IFIH1	Strong	Autosomal dominant	Singleton-Merten syndrome 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFIH1	Orphanet:51	Aicardi-Goutières syndrome
IFIH1	Orphanet:689231	IFIH1-related hereditary spastic paraplegia
IFIH1	Orphanet:85191	Singleton-Merten dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IFIH1	HGNC:18873	ENSG00000115267	Q9BYX4	Interferon-induced helicase C domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFIH1	Interferon-induced helicase C domain-containing protein 1	Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFIH1	Other/Unknown	no		Helicase_C-like, Helicase/UvrB_N, DEATH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
palpebral conjunctiva	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFIH1	276	ubiquitous	marker	palpebral conjunctiva, parotid gland, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFIH1	3,706

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IFIH1	Q9BYX4	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 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
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	878.5×	0.005	IFIH1
TRAF3-dependent IRF activation pathway	1	761.3×	0.005	IFIH1
Modulation of host responses by IFN-stimulated genes	1	601.0×	0.005	IFIH1
TRAF6 mediated NF-kB activation	1	456.8×	0.005	IFIH1
TRAF6 mediated IRF7 activation	1	380.7×	0.005	IFIH1
Dengue virus activates/modulates innate and adaptive immune responses	1	335.9×	0.005	IFIH1
Negative regulators of DDX58/IFIH1 signaling	1	326.3×	0.005	IFIH1
Evasion by RSV of host interferon responses	1	326.3×	0.005	IFIH1
Ovarian tumor domain proteases	1	278.5×	0.005	IFIH1
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.005	IFIH1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	253.8×	0.005	IFIH1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.012	IFIH1
Ub-specific processing proteases	1	53.1×	0.019	IFIH1

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
regulation of type III interferon production	1	8426.0×	0.002	IFIH1
detection of virus	1	4213.0×	0.002	IFIH1
MDA-5 signaling pathway	1	4213.0×	0.002	IFIH1
positive regulation of response to cytokine stimulus	1	2407.4×	0.002	IFIH1
cellular response to exogenous dsRNA	1	1053.2×	0.004	IFIH1
cytoplasmic pattern recognition receptor signaling pathway	1	887.0×	0.004	IFIH1
protein complex oligomerization	1	674.1×	0.004	IFIH1
positive regulation of interferon-alpha production	1	648.1×	0.004	IFIH1
positive regulation of interferon-beta production	1	391.9×	0.005	IFIH1
negative regulation of viral genome replication	1	374.5×	0.005	IFIH1
type I interferon-mediated signaling pathway	1	343.9×	0.005	IFIH1
protein sumoylation	1	324.1×	0.005	IFIH1
antiviral innate immune response	1	227.7×	0.006	IFIH1
cellular response to virus	1	200.6×	0.007	IFIH1
positive regulation of interleukin-6 production	1	166.8×	0.008	IFIH1
positive regulation of tumor necrosis factor production	1	153.2×	0.008	IFIH1
response to virus	1	144.0×	0.008	IFIH1
defense response to virus	1	69.3×	0.015	IFIH1
innate immune response	1	33.6×	0.030	IFIH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IFIH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
IFIH1	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IFIH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IFIH1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.