Is POLE p.Leu2274Val (c.6820C>G) pathogenic?

POLE p.Leu2274Val (c.6820C>G) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-03-30). AlphaMissense: likely benign (0.0707); Rare (popmax 0.887%, afr); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Leu2274Val (c.6820C>G)?

POLE p.Leu2274Val (c.6820C>G) is associated with familial colorectal cancer type X, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Leu2274Val (c.6820C>G) in the general population?

POLE p.Leu2274Val (c.6820C>G) is rare (popmax 0.887%, afr) (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.Leu2274Val (c.6820C>G)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

POLE p.Leu2274Val

c.6820C>G · rs148788180 · VCV240622

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.887%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -4.88	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 2.8	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	11.99	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 0.887% African / African-American · 666/75,052 alleles

Filtering AF 0.832% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.809%

Overall 0.0538% 869/1,613,742 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.887%	113
Admixed American	0.133%	750
Remaining individualsnot grpmax-eligible	0.0848%	1,179
Middle Eastern	0.0662%	1,512
European (non-Finnish)	0.00551%	18,149
South Asian	0.0011%	91,072

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.Leu2274Val
Coding: c.6820C>G
MANE Select: NM_006231
dbSNP: rs148788180
Type: single nucleotide variant
Location: chr12:132624738 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2274: an α-helix; a UniProt-annotated variant site (in imagei)

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: colorectal cancer, susceptibility to, 12 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.Leu2274= 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-leu2274val (accessed [today's date]).

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