Is POLE p.Arg114Ter (c.340C>T) pathogenic?

POLE p.Arg114Ter (c.340C>T) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). Very rare (popmax 8.48e-05%, nfe).

How common is POLE p.Arg114Ter (c.340C>T) in the general population?

POLE p.Arg114Ter (c.340C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

POLE p.Arg114Ter

c.340C>T · rs1555230189 · VCV540728

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 49
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Pangolin	Δ0.58	loss · gain 0.48 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 0.5, phastCons 1
Overall
CADD	44.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,422 alleles

Overall 0.000657% 1/152,144 alleles · very rare

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: POLE
Protein: p.Arg114Ter
Coding: c.340C>T
MANE Select: NM_006231
dbSNP: rs1555230189
Type: single nucleotide variant
Location: chr12:132680037 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 114: an α-helix

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

Similar variants

POLE p.Arg114Gln Uncertain significance ★★ ⚠ same residue
POLE p.Arg114Leu Uncertain significance ★ ⚠ same residue
POLE p.Arg114= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ 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/pole-p-arg114ter (accessed [today's date]).

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