Is POLE p.Pro254Leu (c.761C>T) pathogenic?

POLE p.Pro254Leu (c.761C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1273); Rare (popmax 0.139%, sas); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Pro254Leu (c.761C>T)?

POLE p.Pro254Leu (c.761C>T) is associated with familial colorectal cancer type X, hereditary neoplastic syndrome, Polymerase proofreading-related adenomatous polyposis (ClinVar).

How common is POLE p.Pro254Leu (c.761C>T) in the general population?

POLE p.Pro254Leu (c.761C>T) is rare (popmax 0.139%, sas) (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.Pro254Leu (c.761C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

POLE p.Pro254Leu

c.761C>T · rs200211438 · VCV473829

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 0.51, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.9	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 0.139% South Asian · 127/91,060 alleles

Filtering AF 0.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00948% 153/1,613,912 alleles · rare exomes 140/1,461,782 · genomes 13/152,130 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.139%	717
Remaining individualsnot grpmax-eligible	0.0304%	3,290
East Asian	0.00223%	44,872
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,998
European (non-Finnish)	0.000339%	294,981

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.Pro254Leu
Coding: c.761C>T
MANE Select: NM_006231
dbSNP: rs200211438
Type: single nucleotide variant
Location: chr12:132677403 (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: 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.Pro254= Benign/Likely benign ★★ same residue
POLE p.Pro254Gln Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely 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-pro254leu (accessed [today's date]).

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