Is POLE p.Met2011Arg (c.6032T>G) pathogenic?

POLE p.Met2011Arg (c.6032T>G) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-17). AlphaMissense: likely benign (0.2708); Very rare (popmax 0.0011%, sas).

How common is POLE p.Met2011Arg (c.6032T>G) in the general population?

POLE p.Met2011Arg (c.6032T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about POLE p.Met2011Arg (c.6032T>G)?

AlphaMissense predicts likely benign (score 0.2708) — an in-silico prediction, not a clinical call.

POLE p.Met2011Arg

c.6032T>G · rs2041961084 · VCV949423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2708	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,040 alleles

Overall 6.21e-05% 1/1,611,454 alleles · very rare exomes 1/1,459,212 · genomes 0/152,242 · joint denominator

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.Met2011Arg
Coding: c.6032T>G
MANE Select: NM_006231
dbSNP: rs2041961084
Type: single nucleotide variant
Location: chr12:132632768 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2011: an α-helix; a UniProt-annotated variant site (in imagei)

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

POLE p.Met2011Ile Uncertain significance ★★ ⚠ same residue
POLE p.Met2011Lys Uncertain significance ★★ ⚠ same residue
POLE p.Met2011Val Uncertain significance ★★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ same type

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-met2011arg (accessed [today's date]).

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