POLR1A

Chr 2ADAR

RNA polymerase I subunit A

Also known as: A190, AFDCIN, HLD27, RPA1, RPA190, RPA194, RPO1-4, RPO14

NCBI Gene: 25885 ENSG00000068654 UniProt: O95602 OMIM: 616404

POLR1A encodes the largest catalytic subunit of RNA polymerase I, which transcribes DNA into ribosomal RNA precursors essential for ribosome biogenesis. Mutations cause acrofacial dysostosis Cincinnati type and hypomyelinating leukodystrophy, with both autosomal dominant and autosomal recessive inheritance patterns reported. This gene is highly constrained against loss-of-function variants in the general population, indicating that POLR1A variants are likely to be pathogenic when they do occur.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is the largest subunit of the RNA polymerase I complex. The encoded protein represents the catalytic subunit of the complex, which transcribes DNA into ribosomal RNA precursors. Defects in this gene are a cause of the Cincinnati type of acrofacial dysostosis. [provided by RefSeq, May 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.262 OMIM phenotypes

Clinical Summary— POLR1A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 612 VUS of 1179 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 1.000

Z-score 7.50

OE 0.17 (0.11–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.95Z-score

OE missense 0.74 (0.70–0.79)

750 obs / 1014.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.11–0.26)

0≤0.351.4

Missense OE?0.74 (0.70–0.79)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 16 / 94.8Missense obs/exp: 750 / 1014.2Syn Z: 1.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPOLR1A-related acrofacial dysostosis, Cincinnati typeLOFAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.2796th %ile

LOF

0.63top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 67% of P/LP variants are LoF · LOEUF 0.26

Literature Evidence

LOFPolr1a loss of function led to perturbed ribosome biogenesis and p53-dependent cell death, resulting in a deficiency of neural-crest-derived skeletal precursor cells and consequently craniofacial anomalies. Our findings expand the genotypic and phenotypic heterogeneity of congenital acrofacial disor1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25913037 ↗

ClinVar Variant Classifications

1179 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic8

VUS612

Likely Benign425

Benign81

Conflicting21

Pathogenic

Likely Pathogenic

612

VUS

425

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	6	2	0	0	8
VUS	22	559	26	5	612
Likely Benign	1	9	149	266	425
Benign	1	11	54	15	81
Conflicting	—				21
Total	32	583	229	286	1,151

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap POLR1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →