Is POLE p.Arg47Trp (c.139C>T) pathogenic?

POLE p.Arg47Trp (c.139C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1376); Rare (popmax 0.123%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg47Trp (c.139C>T)?

POLE p.Arg47Trp (c.139C>T) is associated with hereditary neoplastic syndrome, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg47Trp (c.139C>T) in the general population?

POLE p.Arg47Trp (c.139C>T) is rare (popmax 0.123%, nfe) (gnomAD).

What do computational predictors say about POLE p.Arg47Trp (c.139C>T)?

AlphaMissense predicts likely benign (score 0.1376) — an in-silico prediction, not a clinical call.

POLE p.Arg47Trp

c.139C>T · rs143626223 · VCV240391

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.1376 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1376	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -11.35	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.123% European (non-Finnish) · 1,447/1,180,024 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.103% 1,657/1,614,108 alleles · rare exomes 1,534/1,461,874 · genomes 123/152,234 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.877%	114
European (non-Finnish)grpmax	0.123%	815
Finnishnot grpmax-eligible	0.108%	928
Remaining individualsnot grpmax-eligible	0.0768%	1,302
South Asian	0.0549%	1,822
Admixed American	0.03%	3,334
African / African-American	0.02%	5,002
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,801

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg47Trp
Coding: c.139C>T
MANE Select: NM_006231
dbSNP: rs143626223
Type: single nucleotide variant
Location: chr12:132681203 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 47: an α-helix

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: colon carcinoma colorectal cancer, susceptibility to, 12 familial colorectal cancer

Similar variants

POLE p.Arg47Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg47= Likely benign ★★ same residue
POLE p.Arg47Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-arg47trp (accessed [today's date]).

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