Is POLE p.Pro254= (c.762G>A) pathogenic?

POLE p.Pro254= (c.762G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0156%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro254= (c.762G>A)?

POLE p.Pro254= (c.762G>A) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Pro254= (c.762G>A) in the general population?

POLE p.Pro254= (c.762G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

POLE p.Pro254=

c.762G>A · rs371334601 · VCV391007

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -12	GERP -3.1
Overall
CADD	0.144	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,892 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00521% 84/1,613,822 alleles · ultra-rare exomes 79/1,461,794 · genomes 5/152,028 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
European (non-Finnish)	0.00576%	17,352
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Finnishnot grpmax-eligible	0.00313%	31,996
South Asian	0.0022%	45,539
Admixed American	0.00167%	59,986
African / African-American	0.00134%	74,844

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.Pro254=
Coding: c.762G>A
MANE Select: NM_006231
dbSNP: rs371334601
Type: single nucleotide variant
Location: chr12:132677402 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Pro254Gln Uncertain significance ★ ⚠ same residue
POLE p.Pro254Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro254 (accessed [today's date]).

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