POLR3A

Chr 10AR

RNA polymerase III subunit A

Also known as: ADDH, C160, HLD7, RPC1, RPC155, WDRTS, hRPC155

NCBI Gene: 11128 ENSG00000148606 UniProt: O14802 OMIM: 614258

The protein is the catalytic component of RNA polymerase III, which synthesizes small RNAs including tRNAs and rRNAs essential for protein synthesis. Biallelic mutations cause hypomyelinating leukodystrophy 7 (with or without oligodontia and hypogonadotropic hypogonadism) and Wiedemann-Rautenstrauch syndrome through an autosomal recessive inheritance pattern. Mutations can cause disease through dominant-negative effects, where mutant protein interferes with normal RNA polymerase III function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadismMIM #607694

Wiedemann-Rautenstrauch syndromeMIM #264090

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · POLR3A-related disorder · AR · ClinGen 2024
Definitive · odontoleukodystrophy · AR · Illumina
Definitive · Wiedemann-Rautenstrauch syndrome · AR · G2P
Strong · leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism · AR · Labcorp Genetics (formerly Invitae)

+4 more curated pairs

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.88

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — POLR3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.40

OE 0.69 (0.54–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.31Z-score

OE missense 0.76 (0.71–0.82)

574 obs / 752.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.69 (0.54–0.88)

0≤0.351.4

Missense OE?0.76 (0.71–0.82)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 47 / 68.4Missense obs/exp: 574 / 752.0Syn Z: 0.53

Background carrier burden — how many people carry a rare variant somewhere in POLR3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

1,497 rare PASS variants

Rare truncating (LoF)

1 in 680

224 rare PASS variants

Rare synonymous (reference)

1 in 49

661 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POLR3A. 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 79	1 in 630
South Asian	~43k	1 in 47	1 in 680
Remaining (unassigned)	~30k	1 in 54	1 in 890
European (Finnish)	~27k	1 in 230	1 in 1,300
Admixed American	~22k	1 in 45	1 in 1,000
African / African American	~21k	1 in 45	1 in 1,200
East Asian	~20k	1 in 42	1 in 530
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 56	none seen

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.