Is POLE p.Ala581= (c.1743C>T) pathogenic?

POLE p.Ala581= (c.1743C>T) is classified Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-17). Very rare (popmax 0.004%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala581= (c.1743C>T)?

POLE p.Ala581= (c.1743C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala581= (c.1743C>T) in the general population?

POLE p.Ala581= (c.1743C>T) is very rare (popmax 0.004%, afr) (gnomAD).

POLE p.Ala581=

c.1743C>T · rs766396200 · VCV1193362

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -2.9, phastCons 0.54
Overall
CADD	2.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,912 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,971
European (non-Finnish)	0.000169%	590,009

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.Ala581=
Coding: c.1743C>T
MANE Select: NM_006231
dbSNP: rs766396200
Type: single nucleotide variant
Location: chr12:132672266 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 581: an α-helix

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.Ala581Gly Uncertain significance ★★ ⚠ same residue
POLE p.Ala581Ser Uncertain significance ★★ ⚠ same residue
POLE p.Ala581Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ala581Pro Uncertain significance ★ ⚠ same residue
POLE p.Ala581Val 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-ala581 (accessed [today's date]).

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