Is POLE p.Ala15Val (c.44C>T) pathogenic?

POLE p.Ala15Val (c.44C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0831); Very rare (popmax 0.00417%, amr); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ala15Val (c.44C>T)?

POLE p.Ala15Val (c.44C>T) is associated with colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala15Val (c.44C>T) in the general population?

POLE p.Ala15Val (c.44C>T) is very rare (popmax 0.00417%, amr) (gnomAD).

What do computational predictors say about POLE p.Ala15Val (c.44C>T)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

POLE p.Ala15Val

c.44C>T · rs1565986587 · VCV567211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00417%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -7.69	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 0.53	GERP -1.1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	10.17	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 0.00417% Admixed American · 2/47,922 alleles

Filtering AF 0.000692% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000259%

Overall 0.0002% 3/1,500,258 alleles · very rare exomes 1/1,349,218 · genomes 2/151,040 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00417%	23,961
Remaining individualsnot grpmax-eligible	0.00172%	57,990

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.Ala15Val
Coding: c.44C>T
MANE Select: NM_006231
dbSNP: rs1565986587
Type: single nucleotide variant
Location: chr12:132687272 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 15: the 'disordered' region

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Similar variants

POLE p.Ala15= Likely benign ★★ 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
POLE c.1106+4A>G Uncertain significance ★★ same condition
POLE c.1226+3A>G 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-ala15val (accessed [today's date]).

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