Is POLE p.Ser1687Phe (c.5060C>T) pathogenic?

POLE p.Ser1687Phe (c.5060C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.8491); Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser1687Phe (c.5060C>T)?

POLE p.Ser1687Phe (c.5060C>T) is associated with hereditary neoplastic syndrome, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, familial colorectal cancer (ClinVar).

How common is POLE p.Ser1687Phe (c.5060C>T) in the general population?

POLE p.Ser1687Phe (c.5060C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about POLE p.Ser1687Phe (c.5060C>T)?

AlphaMissense predicts likely pathogenic (score 0.8491) — an in-silico prediction, not a clinical call.

POLE p.Ser1687Phe

c.5060C>T · rs1565936909 · VCV644488

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8491	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	29.3	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 0.00134% African / African-American · 1/74,720 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,607,444 alleles · very rare exomes 4/1,455,112 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,720
European (non-Finnish)	0.000255%	392,360

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.Ser1687Phe
Coding: c.5060C>T
MANE Select: NM_006231
dbSNP: rs1565936909
Type: single nucleotide variant
Location: chr12:132642290 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1687: 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

Also linked: facial dysmorphism-immunodeficiency-livedo-short stature syndrome familial colorectal cancer

Similar variants

POLE p.Ser1687Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ser1687Tyr Uncertain significance ★★ ⚠ same residue
POLE p.Ser1687= Uncertain significance ★ same residue
POLE p.Ser1687Cys 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

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-ser1687phe (accessed [today's date]).

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