Charcot-Marie-Tooth disease, demyelinating, IIA 1I

Summary

Charcot-Marie-Tooth disease, demyelinating, IIA 1I (MONDO:0030677) is a disease caused by POLR3B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: POLR3B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, demyelinating, IIA 1I
Mondo ID	MONDO:0030677
OMIM	619742
UMLS	C5676914
MedGen	1811493
GARD	0025607
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease neuropathy, IIA 1I · Charcot-Marie-Tooth disease, demyelinating, IIA 1I · CMT1I

Data availability: 34 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, demyelinating, IIA 1I

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

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

34 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 5 pathogenic/likely pathogenic, 3 benign, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048513	NM_018082.6(POLR3B):c.3137G>A (p.Arg1046His)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2446612	NM_018082.6(POLR3B):c.664C>T (p.Arg222Ter)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31166	NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419962	NM_018082.6(POLR3B):c.2084-6A>G	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488794	NM_018082.6(POLR3B):c.1263+2T>C	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
972978	NM_018082.6(POLR3B):c.1094C>T (p.Ala365Val)	POLR3B	Pathogenic	no assertion criteria provided
1048512	NM_018082.6(POLR3B):c.1124A>T (p.Asp375Val)	POLR3B	Likely pathogenic	criteria provided, single submitter
1341670	NM_018082.6(POLR3B):c.1087G>A (p.Glu363Lys)	POLR3B	Likely pathogenic	criteria provided, single submitter
3233325	NM_018082.6(POLR3B):c.2817_2817+1delinsCT	POLR3B	Likely pathogenic	criteria provided, single submitter
3338027	NM_018082.6(POLR3B):c.847-2A>C	POLR3B	Likely pathogenic	criteria provided, single submitter
3778742	NM_018082.6(POLR3B):c.1370C>T (p.Ser457Phe)	POLR3B	Likely pathogenic	criteria provided, single submitter
4814153	NM_018082.6(POLR3B):c.3260G>A (p.Gly1087Glu)	POLR3B	Likely pathogenic	criteria provided, single submitter
1184077	NM_018082.6(POLR3B):c.3008A>G (p.Tyr1003Cys)	LOC100287944	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184067	NM_018082.6(POLR3B):c.1999G>A (p.Val667Met)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184085	NM_018082.6(POLR3B):c.1324C>T (p.Arg442Cys)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685410	NM_018082.6(POLR3B):c.2045G>A (p.Arg682Lys)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285205	NM_018082.6(POLR3B):c.1244T>C (p.Met415Thr)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31161	NM_018082.6(POLR3B):c.2303G>A (p.Arg768His)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
973230	NM_018082.6(POLR3B):c.2302C>T (p.Arg768Cys)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184072	NM_018082.6(POLR3B):c.2899A>C (p.Ser967Arg)	POLR3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1184087	NM_018082.6(POLR3B):c.1346T>C (p.Leu449Pro)	POLR3B	Uncertain significance	criteria provided, single submitter
2230705	NM_018082.6(POLR3B):c.2740G>A (p.Glu914Lys)	POLR3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068453	NM_018082.6(POLR3B):c.1757C>T (p.Ser586Phe)	POLR3B	Uncertain significance	criteria provided, single submitter
306953	NM_018082.6(POLR3B):c.3390G>C (p.Lys1130Asn)	POLR3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3336790	NM_018082.6(POLR3B):c.2644A>C (p.Lys882Gln)	POLR3B	Uncertain significance	criteria provided, single submitter
3370297	NM_018082.6(POLR3B):c.627G>T (p.Glu209Asp)	POLR3B	Uncertain significance	criteria provided, single submitter
3376862	NM_018082.6(POLR3B):c.2024C>T (p.Pro675Leu)	POLR3B	Uncertain significance	criteria provided, single submitter
3383059	NM_018082.6(POLR3B):c.1996G>A (p.Gly666Ser)	POLR3B	Uncertain significance	criteria provided, single submitter
3777186	NM_018082.6(POLR3B):c.634A>G (p.Ser212Gly)	POLR3B	Uncertain significance	criteria provided, single submitter
4293434	NM_018082.6(POLR3B):c.1485C>G (p.Asn495Lys)	POLR3B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
POLR3B	Strong	Autosomal dominant	Charcot-Marie-Tooth disease, demyelinating, IIA 1I	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR3B	Orphanet:85186	Endosteal sclerosis-cerebellar hypoplasia syndrome
POLR3B	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia 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
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLR3B	DNA-directed RNA polymerase III subunit RPC2	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs 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)
POLR3B	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.

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
endothelial cell	1
esophagus squamous epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3B	5,712

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3B	Q9NW08	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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×	0.005	POLR3B
RNA Polymerase III Transcription Termination	1	496.5×	0.005	POLR3B
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	423.0×	0.005	POLR3B
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	407.9×	0.005	POLR3B
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	407.9×	0.005	POLR3B
RNA Polymerase III Transcription Initiation	1	335.9×	0.005	POLR3B
RNA Polymerase III Transcription	1	326.3×	0.005	POLR3B
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.005	POLR3B
RNA Polymerase III Abortive And Retractive Initiation	1	278.5×	0.005	POLR3B
Innate Immune System	1	25.5×	0.047	POLR3B
Gene expression (Transcription)	1	17.8×	0.061	POLR3B
Immune System	1	13.0×	0.077	POLR3B

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
snRNA transcription by RNA polymerase III	1	1872.4×	0.003	POLR3B
positive regulation of innate immune response	1	526.6×	0.004	POLR3B
positive regulation of interferon-beta production	1	391.9×	0.004	POLR3B
defense response to virus	1	69.3×	0.018	POLR3B
innate immune response	1	33.6×	0.030	POLR3B

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
POLR3B	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	POLR3B

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)
POLR3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.