Is POLE p.Ala724Val (c.2171C>T) pathogenic?

POLE p.Ala724Val (c.2171C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.1614); Ultra-rare (popmax 0.0859%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala724Val (c.2171C>T)?

POLE p.Ala724Val (c.2171C>T) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12, familial colorectal cancer (ClinVar).

How common is POLE p.Ala724Val (c.2171C>T) in the general population?

POLE p.Ala724Val (c.2171C>T) is ultra-rare (popmax 0.0859%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ala724Val (c.2171C>T)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

POLE p.Ala724Val

c.2171C>T · rs61734163 · VCV240427

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0859%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.46	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	33.0	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 0.0859% European (non-Finnish) · 992/1,155,448 alleles

Filtering AF 0.0814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0796%

Overall 0.0673% 1,055/1,567,410 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0859%	1,165
Remaining individualsnot grpmax-eligible	0.0513%	1,948
African / African-American	0.0123%	8,156
South Asian	0.0107%	9,345
Finnishnot grpmax-eligible	0.00956%	10,455
East Asian	0.00912%	10,961
Admixed American	0.00742%	13,470

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.Ala724Val
Coding: c.2171C>T
MANE Select: NM_006231
dbSNP: rs61734163
Type: single nucleotide variant
Location: chr12:132668358 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 724: 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

Also linked: colorectal cancer, susceptibility to, 12 familial colorectal cancer

Similar variants

POLE p.Ala724Glu Uncertain significance ★ ⚠ same residue
POLE p.Ala724Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala724= 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

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-ala724val (accessed [today's date]).

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