Treacher Collins syndrome 4

Summary

Treacher Collins syndrome 4 (MONDO:0030067) is a disease caused by POLR1B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: POLR1B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Treacher Collins syndrome 4
Mondo ID	MONDO:0030067
OMIM	618939
DOID	DOID:0080792
UMLS	C5394546
MedGen	1712280
GARD	0016396
Is cancer (heuristic)	no

Also known as: TCS4 · TREACHER COLLINS SYNDROME 4 · treacher collins syndrome 4 · Treacher-Collins syndrome 4

Data availability: 11 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 › autosomal genetic disease › autosomal dominant disease › Treacher-Collins syndrome › Treacher Collins syndrome 4

Related subtypes (3): Treacher Collins syndrome 1, Treacher Collins syndrome 3, Treacher Collins 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

11 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 3 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
932311	NM_019014.6(POLR1B):c.2046T>A (p.Ser682Arg)	POLR1B	Pathogenic	no assertion criteria provided
932312	NM_019014.6(POLR1B):c.3007C>T (p.Arg1003Cys)	POLR1B	Pathogenic	no assertion criteria provided
932313	NM_019014.6(POLR1B):c.3007C>A (p.Arg1003Ser)	POLR1B	Pathogenic	no assertion criteria provided
3250396	NM_019014.6(POLR1B):c.490G>T (p.Glu164Ter)	POLR1B	Likely pathogenic	criteria provided, single submitter
1705674	NM_019014.6(POLR1B):c.2055C>A (p.Asn685Lys)	POLR1B	Uncertain significance	criteria provided, single submitter
1806005	NM_019014.6(POLR1B):c.1231A>G (p.Met411Val)	POLR1B	Uncertain significance	criteria provided, single submitter
2431488	NM_019014.6(POLR1B):c.56T>C (p.Leu19Ser)	POLR1B	Uncertain significance	criteria provided, single submitter
2444163	NM_019014.6(POLR1B):c.1496C>T (p.Pro499Leu)	POLR1B	Uncertain significance	criteria provided, single submitter
3382286	NM_019014.6(POLR1B):c.921C>G (p.Cys307Trp)	POLR1B	Uncertain significance	criteria provided, single submitter
4293925	NM_019014.6(POLR1B):c.2061_2063dup (p.Tyr687_Gln688insHis)	POLR1B	Uncertain significance	criteria provided, single submitter
4814095	NM_019014.6(POLR1B):c.214C>T (p.Arg72Cys)	POLR1B	Uncertain significance	criteria provided, single submitter

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
POLR1B	Strong	Autosomal dominant	Treacher Collins syndrome 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR1B	Orphanet:861	Treacher-Collins syndrome

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
POLR1B	HGNC:20454	ENSG00000125630	Q9H9Y6	DNA-directed RNA polymerase I subunit RPA2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLR1B	DNA-directed RNA polymerase I subunit RPA2	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.

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)
POLR1B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7

Expression context

Cohort genes with no expression data: 0.

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
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR1B	284	ubiquitous	yes	buccal mucosa cell, sperm, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1B	5,453

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1B	Q9H9Y6	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Positive epigenetic regulation of rRNA expression	1	346.1×	0.008	POLR1B
RNA Polymerase I Transcription Termination	1	326.3×	0.008	POLR1B
RNA Polymerase I Promoter Clearance	1	292.8×	0.008	POLR1B
RNA Polymerase I Transcription	1	285.5×	0.008	POLR1B
Negative epigenetic regulation of rRNA expression	1	259.6×	0.008	POLR1B
RNA Polymerase I Transcription Initiation	1	223.9×	0.008	POLR1B
B-WICH complex positively regulates rRNA expression	1	121.5×	0.011	POLR1B
RNA Polymerase I Promoter Escape	1	121.5×	0.011	POLR1B
NoRC negatively regulates rRNA expression	1	104.8×	0.012	POLR1B
Epigenetic regulation of gene expression	1	71.4×	0.015	POLR1B
Gene expression (Transcription)	1	17.8×	0.056	POLR1B

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
nucleologenesis	1	5617.3×	7e-04	POLR1B
neural crest formation	1	1872.4×	0.001	POLR1B
rRNA transcription	1	991.3×	0.001	POLR1B
embryo implantation	1	351.1×	0.003	POLR1B

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
POLR1B	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	POLR1B

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)
POLR1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.