Is POLE p.Arg446Trp (c.1336C>T) pathogenic?

POLE p.Arg446Trp (c.1336C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.3324); Ultra-rare (popmax 0.029%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg446Trp (c.1336C>T)?

POLE p.Arg446Trp (c.1336C>T) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Arg446Trp (c.1336C>T) in the general population?

POLE p.Arg446Trp (c.1336C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about POLE p.Arg446Trp (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.3324) — an in-silico prediction, not a clinical call.

POLE p.Arg446Trp

c.1336C>T · rs200403177 · VCV421572

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3324 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3324	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -12.81	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.9	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 0.029% East Asian · 13/44,878 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00174% 28/1,613,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
Admixed American	0.00833%	12,005
European (non-Finnish)	0.000847%	117,999

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.Arg446Trp
Coding: c.1336C>T
MANE Select: NM_006231
dbSNP: rs200403177
Type: single nucleotide variant
Location: chr12:132673598 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 446: 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: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Arg446Gly Uncertain significance ★★ same residue
POLE p.Arg446= Benign/Likely benign ★★ same residue
POLE p.Arg446Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg446Leu Uncertain significance ★ ⚠ 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

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-arg446trp (accessed [today's date]).

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