Is POLE p.Ser925Pro (c.2773T>C) pathogenic?

POLE p.Ser925Pro (c.2773T>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.2143); Ultra-rare (popmax 0.0243%, nfe); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Ser925Pro (c.2773T>C)?

POLE p.Ser925Pro (c.2773T>C) is associated with colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser925Pro (c.2773T>C) in the general population?

POLE p.Ser925Pro (c.2773T>C) is ultra-rare (popmax 0.0243%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ser925Pro (c.2773T>C)?

AlphaMissense predicts likely benign (score 0.2143) — an in-silico prediction, not a clinical call.

POLE p.Ser925Pro

c.2773T>C · rs141552148 · VCV240444

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colorectal cancer, susceptibility to, 12

Computational evidence

Protein change
AlphaMissense	0.2143	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -6.30	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 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,961 bp · p 0.18 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0243% European (non-Finnish) · 287/1,180,040 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.0185% 299/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0243%	4,112
Remaining individualsnot grpmax-eligible	0.016%	6,248
Finnishnot grpmax-eligible	0.00312%	32,013

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.Ser925Pro
Coding: c.2773T>C
MANE Select: NM_006231
dbSNP: rs141552148
Type: single nucleotide variant
Location: chr12:132661618 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 925: a UniProt-annotated variant site (in imagei)

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

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Similar variants

POLE p.Ser925Leu Uncertain significance ★★ ⚠ same residue
POLE p.Ser925= Likely benign ★★ same residue
POLE p.Ser925Ter Pathogenic ★ 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

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-ser925pro (accessed [today's date]).

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