Treacher Collins syndrome 2

Summary

Treacher Collins syndrome 2 (MONDO:0013385) is a disease caused by POLR1D (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: POLR1D (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Treacher Collins syndrome 2
Mondo ID	MONDO:0013385
OMIM	613717
DOID	DOID:0080790
UMLS	C3150983
MedGen	462333
GARD	0015698
Is cancer (heuristic)	no

Also known as: POLR1D Treacher-Collins syndrome · TCS2 · Treacher Collins syndrome 2 · Treacher Collins syndrome type 2 · Treacher-Collins syndrome caused by mutation in POLR1D

Data availability: 22 ClinVar variants · 5 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 2

Related subtypes (3): Treacher Collins syndrome 1, Treacher Collins syndrome 3, Treacher Collins syndrome 4

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

22 retrieved; paginated sample, class counts are floors:

7 pathogenic, 7 likely pathogenic, 4 uncertain significance, 2 benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
156464	NM_015972.4(POLR1D):c.163C>G (p.Leu55Val)	POLR1D	Pathogenic	no assertion criteria provided
1697855	NM_015972.4(POLR1D):c.261del (p.Gly88fs)	POLR1D	Pathogenic	no assertion criteria provided
31051	NM_015972.4(POLR1D):c.152T>G (p.Leu51Arg)	POLR1D	Pathogenic	no assertion criteria provided
31052	NM_015972.4(POLR1D):c.326_327del (p.His109fs)	POLR1D	Pathogenic	no assertion criteria provided
31053	NM_015972.4(POLR1D):c.262_263dup (p.Thr89fs)	POLR1D	Pathogenic	no assertion criteria provided
31054	NM_015972.4(POLR1D):c.88_89dup (p.Gln31fs)	POLR1D	Pathogenic	no assertion criteria provided
4683085	NM_015972.4(POLR1D):c.232_233del (p.Ser78fs)	POLR1D	Pathogenic	criteria provided, single submitter
1705417	NM_015972.4(POLR1D):c.89_117del (p.Val30fs)	POLR1D	Likely pathogenic	criteria provided, single submitter
1806833	NM_015972.4(POLR1D):c.60dup (p.Gly21fs)	POLR1D	Likely pathogenic	criteria provided, multiple submitters, no conflicts
31049	NM_015972.4(POLR1D):c.259C>T (p.Arg87Ter)	POLR1D	Likely pathogenic	criteria provided, single submitter
31050	NM_015972.4(POLR1D):c.139G>A (p.Glu47Lys)	POLR1D	Likely pathogenic	criteria provided, single submitter
3899327	NM_015972.4(POLR1D):c.220dup (p.His74fs)	POLR1D	Likely pathogenic	criteria provided, single submitter
4526615	NM_015972.4(POLR1D):c.31del (p.Ile11fs)	POLR1D	Likely pathogenic	criteria provided, single submitter
4814197	NM_015972.4(POLR1D):c.227C>A (p.Ser76Ter)	POLR1D	Likely pathogenic	criteria provided, single submitter
1697036	NM_015972.4(POLR1D):c.329T>C (p.Val110Ala)	POLR1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4716532	NM_015972.4(POLR1D):c.27-8_34del	POLR1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4082094	NM_015972.4(POLR1D):c.26+2T>A	LOC130009445	Uncertain significance	criteria provided, single submitter
1032714	NM_015972.4(POLR1D):c.214A>G (p.Thr72Ala)	POLR1D	Uncertain significance	criteria provided, single submitter
3393144	NM_015972.4(POLR1D):c.388G>T (p.Glu130Ter)	POLR1D	Uncertain significance	criteria provided, single submitter
4070987	NM_015972.4(POLR1D):c.161C>A (p.Ser54Tyr)	POLR1D	Uncertain significance	no assertion criteria provided
1178219	NM_152705.3(POLR1D):c.249G>A (p.Pro83=)	POLR1D	Benign	criteria provided, multiple submitters, no conflicts
1274674	NM_152705.3(POLR1D):c.219G>C (p.Ala73=)	POLR1D	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
POLR1D	Definitive	Autosomal dominant	Treacher Collins syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR1D	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
POLR1D	HGNC:20422	ENSG00000186184	P0DPB5	Protein POLR1D, isoform 2	gencc,clinvar

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)
POLR1D	Other/Unknown	no		POLR1D-like, RNA_pol_Rpb11_13-16kDa_CS, RBP11-like_dimer

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
body of pancreas	1
lower esophagus mucosa	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR1D	288	ubiquitous	marker	body of pancreas, lower esophagus mucosa, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1D	11

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1D	P0DPB5	36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
RNA Polymerase III Chain Elongation	1	634.4×	0.006	POLR1D
RNA Polymerase III Transcription Termination	1	496.5×	0.006	POLR1D
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	423.0×	0.006	POLR1D
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	407.9×	0.006	POLR1D
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	407.9×	0.006	POLR1D
Positive epigenetic regulation of rRNA expression	1	346.1×	0.006	POLR1D
RNA Polymerase III Transcription Initiation	1	335.9×	0.006	POLR1D
RNA Polymerase I Transcription Termination	1	326.3×	0.006	POLR1D
RNA Polymerase III Transcription	1	326.3×	0.006	POLR1D
RNA Polymerase I Promoter Clearance	1	292.8×	0.006	POLR1D
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.006	POLR1D
RNA Polymerase I Transcription	1	285.5×	0.006	POLR1D
RNA Polymerase III Abortive And Retractive Initiation	1	278.5×	0.006	POLR1D
Negative epigenetic regulation of rRNA expression	1	259.6×	0.006	POLR1D
RNA Polymerase I Transcription Initiation	1	223.9×	0.007	POLR1D
B-WICH complex positively regulates rRNA expression	1	121.5×	0.011	POLR1D
RNA Polymerase I Promoter Escape	1	121.5×	0.011	POLR1D
NoRC negatively regulates rRNA expression	1	104.8×	0.012	POLR1D
Epigenetic regulation of gene expression	1	71.4×	0.016	POLR1D
Innate Immune System	1	25.5×	0.043	POLR1D
Gene expression (Transcription)	1	17.8×	0.059	POLR1D
Immune System	1	13.0×	0.077	POLR1D

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
transcription elongation by RNA polymerase I	1	2106.5×	9e-04	POLR1D
transcription by RNA polymerase III	1	766.0×	0.001	POLR1D

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
POLR1D	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	POLR1D

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)
POLR1D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.