Silver-russell syndrome 4

Summary

Silver-russell syndrome 4 (MONDO:0030118) is a disease caused by PLAG1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PLAG1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	silver-russell syndrome 4
Mondo ID	MONDO:0030118
OMIM	618907
UMLS	C5394450
MedGen	1712866
GARD	0018464
Is cancer (heuristic)	no

Also known as: SILVER-RUSSELL SYNDROME 4 · silver-russell syndrome 4 · SRS4

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Silver-Russell syndrome › silver-russell syndrome 4

Related subtypes (10): Russell-silver syndrome, X-linked, Silver-Russell syndrome 3, silver-Russell syndrome due to 7p11.2p13 microduplication, silver-Russell syndrome due to an imprinting defect of 11p15, silver-Russell syndrome due to 11p15 microduplication, silver-Russell syndrome due to maternal uniparental disomy of chromosome 11, silver-Russell syndrome due to maternal uniparental disomy of chromosome 7, Silver-Russell syndrome 5, Silver-Russell syndrome 1, silver-russell 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

8 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
253204	NM_002655.3(PLAG1):c.439del (p.Ser147fs)	LOC126860395	Pathogenic	no assertion criteria provided
253033	NM_002655.3(PLAG1):c.1363del (p.Gln455fs)	PLAG1	Pathogenic	no assertion criteria provided
1687610	NM_002655.3(PLAG1):c.441_489del (p.Ser147fs)	LOC126860395	Likely pathogenic	criteria provided, single submitter
2504817	NM_002655.3(PLAG1):c.589C>T (p.Arg197Ter)	LOC126860395	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292439	NM_002655.3(PLAG1):c.688C>T (p.Arg230Ter)	LOC126860395	Likely pathogenic	criteria provided, single submitter
3775171	NM_002655.3(PLAG1):c.199C>T (p.Gln67Ter)	PLAG1	Likely pathogenic	criteria provided, single submitter
1325824	NM_002655.3(PLAG1):c.758dup (p.Phe254fs)	LOC126860395	Uncertain significance	criteria provided, single submitter
3068518	NM_002655.3(PLAG1):c.545A>T (p.Glu182Val)	LOC126860395	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PLAG1	Strong	Autosomal dominant	silver-russell syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLAG1	Orphanet:276148	Benign epithelial tumor of salivary glands
PLAG1	Orphanet:397590	Silver-Russell syndrome due to a point mutation

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
PLAG1	HGNC:9045	ENSG00000181690	Q6DJT9	Zinc finger protein PLAG1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLAG1	Zinc finger protein PLAG1	Transcription factor whose activation results in up-regulation of target genes, such as IGFII, leading to uncontrolled cell proliferation: when overexpressed in cultured cells, higher proliferation rate and transformation are observed.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLAG1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_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
amniotic fluid	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLAG1	209	ubiquitous	marker	secondary oocyte, amniotic fluid, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLAG1	1,482

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLAG1	Q6DJT9	56.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
gland morphogenesis	1	2407.4×	0.002	PLAG1
prostate gland growth	1	2106.5×	0.002	PLAG1
positive regulation of glial cell proliferation	1	702.2×	0.004	PLAG1
multicellular organism growth	1	137.0×	0.015	PLAG1
negative regulation of gene expression	1	69.1×	0.023	PLAG1
positive regulation of gene expression	1	38.7×	0.034	PLAG1
regulation of DNA-templated transcription	1	31.6×	0.036	PLAG1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	PLAG1

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
PLAG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	PLAG1

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)
PLAG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.