Is POLE p.Ala581Val (c.1742C>T) pathogenic?

POLE p.Ala581Val (c.1742C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-27). AlphaMissense: likely benign (0.2519); Ultra-rare (popmax 0.0121%, sas).

How common is POLE p.Ala581Val (c.1742C>T) in the general population?

POLE p.Ala581Val (c.1742C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about POLE p.Ala581Val (c.1742C>T)?

AlphaMissense predicts likely benign (score 0.2519) — an in-silico prediction, not a clinical call.

POLE p.Ala581Val

c.1742C>T · rs753890723 · VCV1430525

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2519 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2519	likely benign
REVEL	0.4	indeterminate
SaProt	LLR -3.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	22.5	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 0.0121% South Asian · 11/91,080 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000889% 13/1,461,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Ala581Val
Coding: c.1742C>T
MANE Select: NM_006231
dbSNP: rs753890723
Type: single nucleotide variant
Location: chr12:132672267 (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

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.Ala581= Likely benign ★★ same residue
POLE p.Ala581Pro 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

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-ala581val (accessed [today's date]).

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