Is POLE p.Pro282= (c.846C>T) pathogenic?

POLE p.Pro282= (c.846C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1%, afr); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Pro282= (c.846C>T)?

POLE p.Pro282= (c.846C>T) is associated with familial colorectal cancer type X, colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

How common is POLE p.Pro282= (c.846C>T) in the general population?

POLE p.Pro282= (c.846C>T) is low-frequency (popmax 1%, afr) (gnomAD).

How is Familial colorectal cancer Type X inherited?

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

POLE p.Pro282=

c.846C>T · rs5744758 · VCV240632

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1%, afr)

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -3.1, phastCons 0.99
Overall
CADD	5.645	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1% African / African-American · 752/75,010 alleles

Filtering AF 0.943% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.919%

Overall 0.0517% 835/1,613,934 alleles · low-frequency exomes 420/1,461,704 · genomes 415/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1%	100
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed American	0.055%	1,819
South Asian	0.00439%	22,767
European (non-Finnish)	0.000339%	294,970

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.Pro282=
Coding: c.846C>T
MANE Select: NM_006231
dbSNP: rs5744758
Type: single nucleotide variant
Location: chr12:132676609 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome Polymerase proofreading-related adenomatous polyposis intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

For Familial colorectal cancer Type X (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

POLE p.Pro282Ser Uncertain significance ★★ ⚠ same residue
POLE p.Pro282Ala Uncertain significance ★ ⚠ 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

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-pro282 (accessed [today's date]).

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