Is POLE p.Cys2170Arg (c.6508T>C) pathogenic?

POLE p.Cys2170Arg (c.6508T>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-08). AlphaMissense: likely pathogenic (0.8932); Very rare (popmax 0.00374%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Cys2170Arg (c.6508T>C)?

POLE p.Cys2170Arg (c.6508T>C) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Cys2170Arg (c.6508T>C) in the general population?

POLE p.Cys2170Arg (c.6508T>C) is very rare (popmax 0.00374%, nfe) (gnomAD).

What do computational predictors say about POLE p.Cys2170Arg (c.6508T>C)?

AlphaMissense predicts likely pathogenic (score 0.8932) — an in-silico prediction, not a clinical call.

POLE p.Cys2170Arg

c.6508T>C · rs138094751 · VCV473804

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00374%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8932	likely pathogenic
REVEL	0.68	pathogenic-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	24.6	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 0.00374% European (non-Finnish) · 44/1,176,286 alleles

Filtering AF 0.00284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00311% 50/1,605,830 alleles · very rare exomes 45/1,453,642 · genomes 5/152,188 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00483%	20,724
European (non-Finnish)grpmax	0.00374%	26,734
East Asian	0.00224%	44,584
African / African-American	0.00134%	74,692
South Asian	0.00111%	89,918

Remaining individuals 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.Cys2170Arg
Coding: c.6508T>C
MANE Select: NM_006231
dbSNP: rs138094751
Type: single nucleotide variant
Location: chr12:132626140 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2170: a turn; 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: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Cys2170Tyr Uncertain significance ★★ ⚠ same residue
POLE p.Cys2170Gly 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
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-cys2170arg (accessed [today's date]).

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