Is POLE p.Thr889Ser (c.2666C>G) pathogenic?

POLE p.Thr889Ser (c.2666C>G) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-21). AlphaMissense: likely benign (0.1465); Very rare (popmax 0.000847%, nfe); Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

What condition is associated with POLE p.Thr889Ser (c.2666C>G)?

POLE p.Thr889Ser (c.2666C>G) is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

How common is POLE p.Thr889Ser (c.2666C>G) in the general population?

POLE p.Thr889Ser (c.2666C>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about POLE p.Thr889Ser (c.2666C>G)?

AlphaMissense predicts likely benign (score 0.1465) — an in-silico prediction, not a clinical call.

POLE p.Thr889Ser

Q: How is Facial dysmorphism-immunodeficiency-livedo-short stature syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2666C>G · rs768534409 · VCV1805584

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Computational evidence

Protein change
AlphaMissense	0.1465	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,961 bp · p 0.18 · regional, not allelic
Overall
CADD	23.8	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 0.000847% European (non-Finnish) · 10/1,180,006 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,186 alleles · very rare exomes 10/1,461,878 · genomes 0/152,308 · joint denominator

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.Thr889Ser
Coding: c.2666C>G
MANE Select: NM_006231
dbSNP: rs768534409
Type: single nucleotide variant
Location: chr12:132664044 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 889: a β-strand; a UniProt-annotated variant site (in imagei)

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

Disease context

facial dysmorphism-immunodeficiency-livedo-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POLE p.Thr889Asn Uncertain significance ★★ ⚠ same residue
POLE p.Thr889Ile Uncertain significance ★★ ⚠ same residue
POLE p.Thr889Ala Uncertain significance ★ ⚠ same residue
POLE p.Thr889= Likely benign ★ same residue
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.5378+4C>T Uncertain significance ★★ same condition
POLE p.Ala1149Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1323Val 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-thr889ser (accessed [today's date]).

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