Is POLE p.Arg1386Trp (c.4156C>T) pathogenic?

POLE p.Arg1386Trp (c.4156C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.225); Very rare (popmax 0.00144%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg1386Trp (c.4156C>T)?

POLE p.Arg1386Trp (c.4156C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg1386Trp (c.4156C>T) in the general population?

POLE p.Arg1386Trp (c.4156C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about POLE p.Arg1386Trp (c.4156C>T)?

AlphaMissense predicts likely benign (score 0.225) — an in-silico prediction, not a clinical call.

POLE p.Arg1386Trp

c.4156C>T · rs747619107 · VCV581093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.225	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -12.81	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	32.0	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 0.00144% European (non-Finnish) · 17/1,178,980 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00112% 18/1,612,746 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578
European (non-Finnish)grpmax	0.00144%	69,352

Ashkenazi Jewish 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.Arg1386Trp
Coding: c.4156C>T
MANE Select: NM_006231
dbSNP: rs747619107
Type: single nucleotide variant
Location: chr12:132643971 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1386: 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

Similar variants

POLE p.Arg1386Gln Uncertain significance ★★ ⚠ same residue
POLE p.Arg1386Pro Uncertain significance ★★ ⚠ same residue
POLE p.Arg1386Gly Uncertain significance ★ same residue
POLE p.Arg1386= 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-arg1386trp (accessed [today's date]).

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