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

MultiplemechanismADLOEUF 0.161 OMIM phenotype

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

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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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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 OE0.08 (0.05–0.16)

0≤0.351.4

Missense OE0.42 (0.39–0.46)

0≤0.61.4

Synonymous OE1.29

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

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 · 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.PMID:31353023

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.Tyr1PMID:31353023

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