Is POLE p.Ser549Pro (c.1645T>C) pathogenic?

POLE p.Ser549Pro (c.1645T>C) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-20). AlphaMissense: likely pathogenic (0.9869); Ultra-rare (popmax 0.0894%, afr); Associated with familial colorectal cancer.

What condition is associated with POLE p.Ser549Pro (c.1645T>C)?

POLE p.Ser549Pro (c.1645T>C) is associated with familial colorectal cancer, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser549Pro (c.1645T>C) in the general population?

POLE p.Ser549Pro (c.1645T>C) is ultra-rare (popmax 0.0894%, afr) (gnomAD).

What do computational predictors say about POLE p.Ser549Pro (c.1645T>C)?

AlphaMissense predicts likely pathogenic (score 0.9869) — an in-silico prediction, not a clinical call.

POLE p.Ser549Pro

c.1645T>C · rs115558715 · VCV405774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0894%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.9869	likely pathogenic · top 10% in POLE
REVEL	0.593	indeterminate
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	27.8	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 0.0894% African / African-American · 67/74,930 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.00477% 77/1,613,814 alleles · ultra-rare exomes 45/1,461,810 · genomes 32/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0894%	1,118
Remaining individualsnot grpmax-eligible	0.008%	12,500
Admixed American	0.005%	19,997
European (non-Finnish)	0.000169%	589,981

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.Ser549Pro
Coding: c.1645T>C
MANE Select: NM_006231
dbSNP: rs115558715
Type: single nucleotide variant
Location: chr12:132672668 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome

Similar variants

POLE p.Ser549Ala Uncertain significance ★ ⚠ same residue
POLE p.Ser549Phe Uncertain significance ★ ⚠ same residue
POLE p.Ser549= 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

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-ser549pro (accessed [today's date]).

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