Is POLR2E p.Leu135Pro (c.404T>C) pathogenic?

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).

How common is POLR2E p.Leu135Pro (c.404T>C) in the general population?

POLR2E p.Leu135Pro (c.404T>C) is very rare (popmax 0.00831%, nfe) (gnomAD).

What do computational predictors say about POLR2E p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

POLR2E p.Leu135Pro

c.404T>C · rs752979834 · VCV2489438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00831%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 1% in POLR2E
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -13.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,826 bp · p 0.92 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00831% European (non-Finnish) · 98/1,179,988 alleles

Filtering AF 0.00697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00632% 102/1,613,460 alleles · very rare exomes 100/1,461,214 · genomes 2/152,246 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00831%	12,041
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00167%	60,008

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: POLR2E
Protein: p.Leu135Pro
Coding: c.404T>C
MANE Select: NM_002695
dbSNP: rs752979834
Type: single nucleotide variant
Location: chr19:1090933 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.18 · 59 PDB
Residue 135: an α-helix

Full POLR2E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

POLR2E p.Pro53= Benign ★★ same type
POLR2E p.Arg101Gln Uncertain significance ★ ⚠ same type
POLR2E p.Arg162Pro Uncertain significance ★ ⚠ same type
POLR2E p.Arg181Cys Uncertain significance ★ ⚠ same type
POLR2E p.Arg187His Uncertain significance ★ ⚠ same type
POLR2E p.Arg24Cys Uncertain significance ★ ⚠ same type
POLR2E p.Arg52Gln Uncertain significance ★ ⚠ same type
POLR2E p.Asp120Asn Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/polr2e-p-leu135pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown