Is POLE p.Arg249Ter (c.745C>T) pathogenic?

POLE p.Arg249Ter (c.745C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg249Ter (c.745C>T)?

POLE p.Arg249Ter (c.745C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg249Ter (c.745C>T) in the general population?

POLE p.Arg249Ter (c.745C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

POLE p.Arg249Ter

c.745C>T · rs769190256 · VCV566551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 49
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.47	loss · gain 0.07 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.5	GERP 0.49, phastCons 1
Overall
CADD	37.0	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 0.00668% East Asian · 3/44,896 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000991% 16/1,613,814 alleles · very rare exomes 15/1,461,748 · genomes 1/152,066 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
Admixed American	0.00167%	59,994
Finnishnot grpmax-eligible	0.00156%	63,994
African / African-American	0.00134%	74,868
European (non-Finnish)	0.000848%	117,991

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.Arg249Ter
Coding: c.745C>T
MANE Select: NM_006231
dbSNP: rs769190256
Type: single nucleotide variant
Location: chr12:132677419 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Arg249Gln Uncertain significance ★★ ⚠ same residue
POLE p.Arg249Gly Uncertain significance ★ ⚠ same residue
POLE p.Arg249Leu Uncertain significance ★ same residue
POLE p.Arg249= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ same condition

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-arg249ter (accessed [today's date]).

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