POLR3B

Chr 12ADAR

RNA polymerase III subunit B

Also known as: C128, CMT1I, HLD8, INMAP, RPC2

NCBI Gene: 55703 ENSG00000013503 UniProt: Q9NW08 OMIM: 614366

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the second largest subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The largest subunit and the encoded protein form the catalytic center of RNA polymerase III. Mutations in this gene are a cause of hypomyelinating leukodystrophy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.872 OMIM phenotypes

Clinical Summary— POLR3B

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Gene-Disease Validity (ClinGen)

POLR3B-related disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

77 unique Pathogenic / Likely Pathogenic· 356 VUS of 774 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — POLR3B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.46

OE 0.68 (0.54–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.20Z-score

OE missense 0.64 (0.59–0.70)

402 obs / 627.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.68 (0.54–0.87)

0≤0.351.4

Missense OE?0.64 (0.59–0.70)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 47 / 69.0Missense obs/exp: 402 / 627.4Syn Z: 0.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPOLR3B-related neurodevelopmental disorder with or without seizures, ataxia, spasticity, and demyelinating neuropathyOTHERAD

definitivePOLR3B-related leukodystrophy, hypomyelinating with or without oligodontia and/or hypogonadotropic hypogonadismLOFAR

This gene — mechanism propensity

0.7036th %ile

GOF

0.4973th %ile

LOF

0.4234th %ile

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.

DNprediction above median

LOF57% of P/LP variants are LoF

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

774 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic49

VUS356

Likely Benign181

Benign73

Conflicting37

Pathogenic

Likely Pathogenic

356

VUS

181

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	12	1	0	28
Likely Pathogenic	29	17	3	0	49
VUS	3	302	38	13	356
Likely Benign	0	5	92	84	181
Benign	0	1	70	2	73
Conflicting	—				37
Total	47	337	204	99	724

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap POLR3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →