Is POLE p.Ala716Val (c.2147C>T) pathogenic?

POLE p.Ala716Val (c.2147C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.3261); Very rare (popmax 0.00226%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala716Val (c.2147C>T)?

POLE p.Ala716Val (c.2147C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala716Val (c.2147C>T) in the general population?

POLE p.Ala716Val (c.2147C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about POLE p.Ala716Val (c.2147C>T)?

AlphaMissense predicts likely benign (score 0.3261) — an in-silico prediction, not a clinical call.

POLE p.Ala716Val

c.2147C>T · rs567031389 · VCV405671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3261	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.7	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 0.00226% East Asian · 1/44,324 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000313% 5/1,595,676 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,324
Remaining individualsnot grpmax-eligible	0.00162%	61,648
African / African-American	0.00135%	74,156
European (non-Finnish)	0.000171%	585,199

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.Ala716Val
Coding: c.2147C>T
MANE Select: NM_006231
dbSNP: rs567031389
Type: single nucleotide variant
Location: chr12:132668382 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 716: 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.Ala716Glu Uncertain significance ★★ ⚠ same residue
POLE p.Ala716Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ala716= Likely benign ★ same residue
POLE p.Ala716Ser Uncertain significance ★★ ⚠ same residue
POLE p.Ala716Pro Uncertain significance ★ ⚠ 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

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-ala716val (accessed [today's date]).

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