Is POLE p.Leu32Phe (c.94C>T) pathogenic?

POLE p.Leu32Phe (c.94C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1175); Ultra-rare (popmax 0.0483%, amr); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Leu32Phe (c.94C>T)?

POLE p.Leu32Phe (c.94C>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.Leu32Phe (c.94C>T) in the general population?

POLE p.Leu32Phe (c.94C>T) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about POLE p.Leu32Phe (c.94C>T)?

AlphaMissense predicts likely benign (score 0.1175) — an in-silico prediction, not a clinical call.

POLE p.Leu32Phe

c.94C>T · rs781513537 · VCV240634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.1175	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.66	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 6.3	GERP -0.74, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	12.31	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 0.0483% Admixed American · 29/60,010 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00186% 30/1,614,098 alleles · ultra-rare exomes 28/1,461,868 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0483%	2,069
European (non-Finnish)	8.47e-05%	1,180,044

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.Leu32Phe
Coding: c.94C>T
MANE Select: NM_006231
dbSNP: rs781513537
Type: single nucleotide variant
Location: chr12:132681248 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 32: an α-helix

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.Leu32Arg Uncertain significance ★★ ⚠ same residue
POLE p.Leu32Pro Uncertain significance ★★ ⚠ same residue
POLE p.Leu32Val Uncertain significance ★★ ⚠ same residue
POLE p.Leu32= 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

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-leu32phe (accessed [today's date]).

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