Is POLE p.Pro1549= (c.4647C>A) pathogenic?

POLE p.Pro1549= (c.4647C>A) is classified Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro1549= (c.4647C>A)?

POLE p.Pro1549= (c.4647C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro1549= (c.4647C>A) in the general population?

POLE p.Pro1549= (c.4647C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

POLE p.Pro1549=

c.4647C>A · rs1004972253 · VCV1100363

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

hereditary neoplastic syndrome

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 -4.2	GERP -3.2
Overall
CADD	0.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,920 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,520 alleles · very rare exomes 2/1,461,282 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,460
European (non-Finnish)	8.48e-05%	1,179,832

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.Pro1549=
Coding: c.4647C>A
MANE Select: NM_006231
dbSNP: rs1004972253
Type: single nucleotide variant
Location: chr12:132642901 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1549: a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.Pro1549Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ 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-pro1549 (accessed [today's date]).

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