POLR2A

Chr 17AD

RNA polymerase II subunit A

Also known as: NEDHIB, POLR2, POLRA, RPB1, RPBh1, RPO2, RPOL2, RpIILS

NCBI Gene: 5430 ENSG00000181222 UniProt: P24928 OMIM: 180660

This gene encodes the largest subunit of RNA polymerase II, which synthesizes messenger RNA and many functional non-coding RNAs by catalyzing the formation of phosphodiester bonds during transcription. Mutations cause a neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.16), reflecting its essential role in transcription.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— POLR2A

🧬

Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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.

📋

ClinVar Variants

45 unique Pathogenic / Likely Pathogenic· 360 VUS of 561 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 7.72

OE 0.08 (0.05–0.16)

Highly constrained

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

Missense Constraint?

7.13Z-score

OE missense 0.42 (0.39–0.46)

512 obs / 1210.0 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.05–0.16)

0≤0.351.4

Missense OE?0.42 (0.39–0.46)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 7 / 82.8Missense obs/exp: 512 / 1210.0Syn Z: -5.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePOLR2A-related syndromic intellectual disabilityOTHERAD

limitedPOLR2A-related predisposition to ependymomaOTHERAD

This gene — mechanism propensity

0.4488th %ile

GOF

0.4875th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 27% of P/LP variants are LoF · LOEUF 0.16

DN1 literature citation

Literature Evidence

DNWe conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.1

LOFAltogether, structural evaluation of POLR2A variants resulted in the expected haploinsufficiency for p.Gln700Ã¢Ëâ and p.Gln735Ã¢Ëâ, putative haploinsufficiency for the IF deletions, and an expected dominant-negative effect for the missense variants p.Ile457Thr, p.Thr736Met, p.Met769Thr, p.Tyr11

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 31353023 ↗

ClinVar Variant Classifications

561 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic37

VUS360

Likely Benign95

Benign20

Conflicting9

Pathogenic

Likely Pathogenic

360

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	4	0	0	8
Likely Pathogenic	8	29	0	0	37
VUS	24	323	12	1	360
Likely Benign	1	16	8	70	95
Benign	0	0	8	12	20
Conflicting	—				9
Total	37	372	28	83	529

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap POLR2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →