POLR3B
Chr 12ADARRNA polymerase III subunit B
Also known as: C128, CMT1I, HLD8, INMAP, RPC2
This gene encodes the second largest subunit of RNA polymerase III, which synthesizes transfer RNAs and small ribosomal RNAs and forms part of the enzyme's catalytic center. Mutations cause hypomyelinating leukodystrophy type 8 (with or without oligodontia and hypogonadism) and demyelinating Charcot-Marie-Tooth disease type 1I through both autosomal recessive and autosomal dominant inheritance patterns. The gene shows tolerance to loss-of-function variants, suggesting mutations can cause disease through multiple mechanisms depending on the specific variant type.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
497 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 8 | 4 | 4 | 0 | 16 |
Likely Pathogenic | 18 | 9 | 2 | 0 | 29 |
VUS | 2 | 225 | 26 | 9 | 262 |
Likely Benign | 0 | 0 | 48 | 60 | 108 |
Benign | 0 | 0 | 10 | 0 | 10 |
Conflicting | — | 22 | |||
| Total | 28 | 238 | 90 | 69 | 447 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
POLR3B · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools