Is POLE p.Val2250Phe (c.6748G>T) pathogenic?

POLE p.Val2250Phe (c.6748G>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-07). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val2250Phe (c.6748G>T)?

POLE p.Val2250Phe (c.6748G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Val2250Phe (c.6748G>T) in the general population?

POLE p.Val2250Phe (c.6748G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about POLE p.Val2250Phe (c.6748G>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

POLE p.Val2250Phe

c.6748G>T · rs756931710 · VCV1517830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	23.7	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 0.00134% African / African-American · 1/74,810 alleles

Overall 0.000124% 2/1,608,708 alleles · very rare exomes 1/1,456,486 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,810
South Asian	0.0011%	90,970

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.Val2250Phe
Coding: c.6748G>T
MANE Select: NM_006231
dbSNP: rs756931710
Type: single nucleotide variant
Location: chr12:132624810 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2250: an α-helix; 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.Val2250Ala Uncertain significance ★★ ⚠ same residue
POLE p.Val2250Ile Uncertain significance ★★ ⚠ same residue
POLE p.Val2250Leu Uncertain significance ★★ ⚠ same residue
POLE p.Val2250= 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-val2250phe (accessed [today's date]).

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