Singleton-Merten syndrome 2

Summary

Singleton-Merten syndrome 2 (MONDO:0014575) is a disease caused by RIGI (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RIGI (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Singleton-Merten syndrome 2
Mondo ID	MONDO:0014575
OMIM	616298
UMLS	C4225380
MedGen	907372
GARD	0016078
Is cancer (heuristic)	no

Also known as: DDX58 singleton-Merten dysplasia · SGMRT2 · singleton-Merten dysplasia caused by mutation in DDX58 · singleton-Merten syndrome 2 · singleton-Merten syndrome type 2

Data availability: 20 ClinVar variants · 4 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 2

Related subtypes (1): Singleton-Merten syndrome 1

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

20 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 6 benign, 2 pathogenic, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
189344	NM_014314.4(RIGI):c.1118A>C (p.Glu373Ala)	RIGI	Pathogenic	no assertion criteria provided
189345	NM_014314.4(RIGI):c.803G>T (p.Cys268Phe)	RIGI	Pathogenic	no assertion criteria provided
802476	NM_014314.4(RIGI):c.1529A>T (p.Glu510Val)	RIGI	Likely pathogenic	criteria provided, single submitter
931225	NM_014314.4(RIGI):c.2368A>C (p.Ile790Leu)	LOC101060445	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039146	NM_014314.4(RIGI):c.2728G>T (p.Asp910Tyr)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057374	NM_014314.4(RIGI):c.816dup (p.Val273fs)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341799	NM_014314.4(RIGI):c.1232C>T (p.Ser411Leu)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
1424855	NM_014314.4(RIGI):c.298T>G (p.Leu100Val)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
1493909	NM_014314.4(RIGI):c.2596C>T (p.Arg866Ter)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
2688922	NM_014314.4(RIGI):c.877G>C (p.Val293Leu)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
931785	NM_014314.4(RIGI):c.1863G>T (p.Glu621Asp)	RIGI	Uncertain significance	criteria provided, single submitter
932023	NM_014314.4(RIGI):c.396_399del (p.Asn133fs)	RIGI	Uncertain significance	criteria provided, multiple submitters, no conflicts
1166851	NM_014314.4(RIGI):c.2337+11G>A	RIGI	Benign	criteria provided, multiple submitters, no conflicts
1166894	NM_014314.4(RIGI):c.1376-21dup	RIGI	Benign	criteria provided, multiple submitters, no conflicts
1168118	NM_014314.4(RIGI):c.1740T>A (p.Asp580Glu)	RIGI	Benign	criteria provided, multiple submitters, no conflicts
1169347	NM_014314.4(RIGI):c.2400A>C (p.Val800=)	RIGI	Benign	criteria provided, multiple submitters, no conflicts
1255473	NM_014314.4(RIGI):c.1481-21dup	RIGI	Benign	criteria provided, multiple submitters, no conflicts
713116	NM_014314.4(RIGI):c.1059C>T (p.Asn353=)	RIGI	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
719465	NM_014314.4(RIGI):c.734A>G (p.Asn245Ser)	RIGI	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
786134	NM_014314.4(RIGI):c.1737C>T (p.Phe579=)	RIGI	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
RIGI	Strong	Autosomal dominant	Singleton-Merten syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIGI	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
RIGI	HGNC:19102	ENSG00000107201	O95786	Antiviral innate immune response receptor RIG-I	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIGI	Antiviral innate immune response receptor RIG-I	Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIGI	Enzyme (other)	yes	3.6.4.13	Helicase_C-like, DEATH-like_dom_sf, DEAD/DEAH_box_helicase_dom

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
buccal mucosa cell	1
tendon of biceps brachii	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIGI	269	ubiquitous	marker	buccal mucosa cell, upper leg skin, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIGI	6,038

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RIGI	O95786	44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
OAS antiviral response	1	1268.9×	0.005	RIGI
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	878.5×	0.005	RIGI
TRAF3-dependent IRF activation pathway	1	761.3×	0.005	RIGI
Modulation of host responses by IFN-stimulated genes	1	601.0×	0.005	RIGI
TRAF6 mediated NF-kB activation	1	456.8×	0.005	RIGI
TRAF6 mediated IRF7 activation	1	380.7×	0.005	RIGI
Negative regulators of DDX58/IFIH1 signaling	1	326.3×	0.005	RIGI
Evasion by RSV of host interferon responses	1	326.3×	0.005	RIGI
Ovarian tumor domain proteases	1	278.5×	0.005	RIGI
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.005	RIGI
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	253.8×	0.005	RIGI
RSV-host interactions	1	156.4×	0.008	RIGI
ISG15 antiviral mechanism	1	150.3×	0.008	RIGI
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.012	RIGI
Ub-specific processing proteases	1	53.1×	0.019	RIGI

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	RIGI
detection of virus	1	4213.0×	0.002	RIGI
positive regulation of myeloid dendritic cell cytokine production	1	2808.7×	0.002	RIGI
RIG-I signaling pathway	1	2407.4×	0.002	RIGI
positive regulation of response to cytokine stimulus	1	2407.4×	0.002	RIGI
cellular response to exogenous dsRNA	1	1053.2×	0.003	RIGI
positive regulation of granulocyte macrophage colony-stimulating factor production	1	991.3×	0.003	RIGI
cytoplasmic pattern recognition receptor signaling pathway	1	887.0×	0.003	RIGI
positive regulation of interferon-alpha production	1	648.1×	0.004	RIGI
positive regulation of defense response to virus by host	1	526.6×	0.004	RIGI
response to exogenous dsRNA	1	526.6×	0.004	RIGI
positive regulation of interferon-beta production	1	391.9×	0.005	RIGI
positive regulation of interleukin-8 production	1	244.2×	0.007	RIGI
antiviral innate immune response	1	227.7×	0.007	RIGI
positive regulation of interleukin-6 production	1	166.8×	0.009	RIGI
regulation of cell migration	1	157.5×	0.009	RIGI
positive regulation of tumor necrosis factor production	1	153.2×	0.009	RIGI
response to virus	1	144.0×	0.009	RIGI
gene expression	1	79.9×	0.015	RIGI
defense response to virus	1	69.3×	0.017	RIGI
positive regulation of gene expression	1	38.7×	0.028	RIGI
innate immune response	1	33.6×	0.031	RIGI
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	RIGI

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
RIGI	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RIGI	3.6.4.13	RNA helicase

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

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)
RIGI	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.