POLR3D

Chr 8

RNA polymerase III subunit D

Also known as: BN51T, C53, RPC4, RPC53, TSBN51

NCBI Gene: 661 ENSG00000168495 UniProt: P05423 OMIM: 187280

The protein serves as a specific peripheral component of RNA polymerase III, which transcribes small non-coding RNAs including tRNAs, 5S rRNA, and microRNAs, and also functions as a DNA sensor in innate immune responses. Mutations cause autosomal recessive hypomyelinating leukodystrophy, typically presenting in early childhood with progressive motor deterioration, developmental delay, and cerebellar ataxia. The gene shows extremely high constraint against loss-of-function variants, indicating that such mutations are likely pathogenic when found in patients with compatible clinical presentations.

OMIM ResearchSummary from RefSeq, UniProt

This gene complements a temperature-sensitive mutant isolated from the BHK-21 Syrian hamster cell line. It leads to a block in progression through the G1 phase of the cell cycle at nonpermissive temperatures. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.25

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.68

OE 0.84 (0.58–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.36Z-score

OE missense 0.93 (0.83–1.05)

195 obs / 209.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.58–1.25)

0≤0.351.4

Missense OE?0.93 (0.83–1.05)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 18 / 21.4Missense obs/exp: 195 / 209.6Syn Z: -0.80

Background carrier burden — how many people carry a rare variant somewhere in POLR3D?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

558 rare PASS variants

Rare truncating (LoF)

1 in 1,200

95 rare PASS variants

Rare synonymous (reference)

1 in 180

231 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POLR3D. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 1,100
South Asian	~43k	1 in 75	1 in 1,300
Remaining (unassigned)	~30k	1 in 120	1 in 1,400
European (Finnish)	~27k	1 in 560	1 in 3,600
Admixed American	~22k	1 in 110	1 in 1,300
African / African American	~21k	1 in 100	1 in 1,700
East Asian	~20k	1 in 130	1 in 1,500
Ashkenazi Jewish	~13k	1 in 460	≈ 1 in 3,600
Middle Eastern	~2,884	1 in 180	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 8.? see exons ↓