Is POLE p.Leu424Val (c.1270C>G) pathogenic?

POLE p.Leu424Val (c.1270C>G) is classified Pathogenic in POLE (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-08). AlphaMissense: likely pathogenic (0.9565); Very rare (popmax 8.47e-05%, nfe); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Leu424Val (c.1270C>G)?

POLE p.Leu424Val (c.1270C>G) is associated with familial colorectal cancer type X, cystic fibrosis-gastritis-megaloblastic anemia syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Leu424Val (c.1270C>G) in the general population?

POLE p.Leu424Val (c.1270C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Familial colorectal cancer Type X inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about POLE p.Leu424Val (c.1270C>G)?

AlphaMissense predicts likely pathogenic (score 0.9565) — an in-silico prediction, not a clinical call.

POLE p.Leu424Val

c.1270C>G · rs483352909 · VCV40046

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9565 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
AlphaMissense	0.9565	likely pathogenic ✓ concordant with ClinVar
REVEL	0.654	pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.4	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 8.47e-05% European (non-Finnish) · 1/1,179,986 alleles

Overall 6.2e-05% 1/1,614,018 alleles · very rare exomes 1/1,461,680 · genomes 0/152,338 · joint denominator

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.Leu424Val
Coding: c.1270C>G
MANE Select: NM_006231
dbSNP: rs483352909
Type: single nucleotide variant
Location: chr12:132673664 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 424: an α-helix; a UniProt-annotated variant site (in crcs12)

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

Disease context

familial colorectal cancer type X — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cystic fibrosis-gastritis-megaloblastic anemia syndrome colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome Polymerase proofreading-related adenomatous polyposis

For Familial colorectal cancer Type X (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

POLE p.Leu424Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Leu424Ile Uncertain significance ★ ⚠ same residue
POLE p.Leu424= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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

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-leu424val (accessed [today's date]).

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