POLR2A

Chr 17

RNA polymerase II subunit A

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

NCBI Gene: 5430 ENSG00000181222 UniProt: P24928

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]

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

541

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— POLR2A

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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.

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ClinVar Variants

69 Pathogenic / Likely Pathogenic· 355 VUS of 541 total submissions

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.05–0.16)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.42 (0.39–0.46)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.29

0≤1.21.6

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