# NM_002695.5(POLR2E):c.404T>C (p.Leu135Pro)

https://sugi.bio/variant/polr2e-p-leu135pro

## Summary

**POLR2E p.Leu135Pro (c.404T>C)** is classified **Uncertain significance** in POLR2E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.9995); Very rare (popmax 0.00831%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs752979834 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00831%, nfe)

## For patients & families {#patients}

This is a change in the POLR2E gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POLR2E](https://sugi.bio/atlas/gene/POLR2E/) |
| Protein change (HGVS p.) | p.Leu135Pro |
| Coding change (HGVS c.) | c.404T>C |
| MANE Select transcript | [NM_002695](https://www.ncbi.nlm.nih.gov/nuccore/NM_002695) |
| dbSNP | [rs752979834](https://www.ncbi.nlm.nih.gov/snp/rs752979834/) |
| Variant type | single nucleotide variant |
| Location | chr19:1090933-1090933 (GRCh38) |
| ClinVar | [VCV2489438](https://www.ncbi.nlm.nih.gov/clinvar/variation/2489438/) |

**All HGVS expressions:** `NC_000019.10:g.1090933A>G`, `NC_000019.9:g.1090932A>G`, `NM_001316323.2:c.125T>C`, `NM_001316324.2:c.125T>C`, `NM_002695.5:c.404T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9995)
- REVEL 0.816 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.719 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.845, GERP 1.3, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in POLR2E (of 1,237 modeled).
- CADD: **PHRED 28.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (1,089,489–1,095,315), spanning 5,826 bp. Chi-square p 0.92. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00831%** (nfe) · FAF95 0.00697% · FAF99 0.00641% · 98/1,179,988 in the highest group · 102/1,613,460 alleles overall — very rare (popmax 0.00831%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00831% | 12,041 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| Admixed American | 0.00167% | 60,008 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**POLR2E** population constraint: LOEUF 1.522, pLI 2.7362e-12, missense-Z 0.25804. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **135** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.18, 89% of residues very-high.

**59 experimental structure(s)** (PDB): [28JC](https://www.rcsb.org/structure/28JC), [5IY6](https://www.rcsb.org/structure/5IY6), [5IY7](https://www.rcsb.org/structure/5IY7), [5IY8](https://www.rcsb.org/structure/5IY8), [5IY9](https://www.rcsb.org/structure/5IY9), [5IYA](https://www.rcsb.org/structure/5IYA).

## What this gene does {#gene-function}

*Describes the biological roles of POLR2E (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** POLR2E participates in disease-associated pathways. In Reactome, POLR2E is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**, **Viral Messenger RNA Synthesis**.

**Disease mechanism (Reactome):** POLR2E loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481), [Viral Messenger RNA Synthesis](https://reactome.org/content/detail/R-HSA-168325), [Abortive elongation of HIV-1 transcript in the absence of Tat](https://reactome.org/content/detail/R-HSA-167242).

### Pathways affected {#pathways}

POLR2E participates in **56 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| ⚕ [Viral Messenger RNA Synthesis](https://reactome.org/content/detail/R-HSA-168325) | curated |
| ⚕ [Abortive elongation of HIV-1 transcript in the absence of Tat](https://reactome.org/content/detail/R-HSA-167242) | electronic |
| ⚕ [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152) | electronic |
| ⚕ [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200) | electronic |
| ⚕ [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158) | electronic |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [HIV elongation arrest and recovery](https://reactome.org/content/detail/R-HSA-167287) | electronic |
| ⚕ [Pausing and recovery of HIV elongation](https://reactome.org/content/detail/R-HSA-167290) | electronic |
| ⚕ [Pausing and recovery of Tat-mediated HIV elongation](https://reactome.org/content/detail/R-HSA-167238) | electronic |
| ⚕ [RNA Pol II CTD phosphorylation and interaction with CE during HIV infection](https://reactome.org/content/detail/R-HSA-167160) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Signaling by FGFR2 IIIa TM](https://reactome.org/content/detail/R-HSA-8851708) | electronic |
| ⚕ [Tat-mediated HIV elongation arrest and recovery](https://reactome.org/content/detail/R-HSA-167243) | electronic |
| ⚕ [Tat-mediated elongation of the HIV-1 transcript](https://reactome.org/content/detail/R-HSA-167246) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [B-WICH complex positively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-5250924) | curated |
| [Cytosolic sensors of pathogen-associated DNA ](https://reactome.org/content/detail/R-HSA-1834949) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [FGFR2 alternative splicing](https://reactome.org/content/detail/R-HSA-6803529) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Formation of the Early Elongation Complex](https://reactome.org/content/detail/R-HSA-113418) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | curated |
| [MicroRNA (miRNA) biogenesis](https://reactome.org/content/detail/R-HSA-203927) | curated |
| [Processing of Capped Intron-Containing Pre-mRNA](https://reactome.org/content/detail/R-HSA-72203) | curated |
| [RNA Pol II CTD phosphorylation and interaction with CE](https://reactome.org/content/detail/R-HSA-77075) | curated |
| [RNA Polymerase I Promoter Escape](https://reactome.org/content/detail/R-HSA-73772) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [Transcriptional regulation by small RNAs](https://reactome.org/content/detail/R-HSA-5578749) | curated |
| [mRNA Capping](https://reactome.org/content/detail/R-HSA-72086) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |
| [mRNA Splicing - Minor Pathway](https://reactome.org/content/detail/R-HSA-72165) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |
| [PIWI-interacting RNA (piRNA) biogenesis](https://reactome.org/content/detail/R-HSA-5601884) | electronic |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | electronic |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | electronic |
| [RNA Polymerase III Abortive And Retractive Initiation](https://reactome.org/content/detail/R-HSA-749476) | electronic |
| [RNA Polymerase III Chain Elongation](https://reactome.org/content/detail/R-HSA-73780) | electronic |
| [RNA Polymerase III Transcription Initiation From Type 1 Promoter](https://reactome.org/content/detail/R-HSA-76061) | electronic |
| [RNA Polymerase III Transcription Initiation From Type 2 Promoter](https://reactome.org/content/detail/R-HSA-76066) | electronic |
| [RNA Polymerase III Transcription Initiation From Type 3 Promoter](https://reactome.org/content/detail/R-HSA-76071) | electronic |
| [RNA Polymerase III Transcription Termination](https://reactome.org/content/detail/R-HSA-73980) | electronic |
| [RNA polymerase II transcribes snRNA genes](https://reactome.org/content/detail/R-HSA-6807505) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** transcription elongation by RNA polymerase I, transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter, transcription elongation by RNA polymerase II, transcription by RNA polymerase III, transcription initiation at RNA polymerase III promoter.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related POLR2E variant pages (same residue, condition, or type): [POLR2E p.Pro53=](/variant/polr2e-p-pro53), [POLR2E p.Arg101Gln](/variant/polr2e-p-arg101gln), [POLR2E p.Arg162Pro](/variant/polr2e-p-arg162pro), [POLR2E p.Arg181Cys](/variant/polr2e-p-arg181cys), [POLR2E p.Arg187His](/variant/polr2e-p-arg187his), [POLR2E p.Arg24Cys](/variant/polr2e-p-arg24cys), [POLR2E p.Arg52Gln](/variant/polr2e-p-arg52gln), [POLR2E p.Asp120Asn](/variant/polr2e-p-asp120asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2489438). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*