Is POLE p.Arg2145Ter (c.6433C>T) pathogenic?

POLE p.Arg2145Ter (c.6433C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-09). Very rare (popmax 0.00549%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg2145Ter (c.6433C>T)?

POLE p.Arg2145Ter (c.6433C>T) is associated with hereditary neoplastic syndrome, familial colorectal cancer (ClinVar).

How common is POLE p.Arg2145Ter (c.6433C>T) in the general population?

POLE p.Arg2145Ter (c.6433C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

POLE p.Arg2145Ter

c.6433C>T · rs1451513451 · VCV584829

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

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 46 of 49
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Overall
CADD	43.0	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 0.00549% South Asian · 5/91,066 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,613,720 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,213
Admixed American	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	8.47e-05%	1,180,025

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.Arg2145Ter
Coding: c.6433C>T
MANE Select: NM_006231
dbSNP: rs1451513451
Type: single nucleotide variant
Location: chr12:132626215 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2145: a UniProt-annotated variant site (in imagei)

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

Also linked: familial colorectal cancer

Similar variants

POLE p.Arg2145Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg2145Pro Uncertain significance ★ ⚠ same residue
POLE p.Arg2145= 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
POLE c.1106+4A>G 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-arg2145ter (accessed [today's date]).

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