Is POLE p.Pro677Leu (c.2030C>T) pathogenic?

POLE p.Pro677Leu (c.2030C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-20). AlphaMissense: ambiguous (0.3843); Very rare (popmax 0.000171%, nfe); Associated with POLE-related disorder.

What condition is associated with POLE p.Pro677Leu (c.2030C>T)?

POLE p.Pro677Leu (c.2030C>T) is associated with POLE-related disorder (ClinVar).

How common is POLE p.Pro677Leu (c.2030C>T) in the general population?

POLE p.Pro677Leu (c.2030C>T) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about POLE p.Pro677Leu (c.2030C>T)?

AlphaMissense predicts ambiguous (score 0.3843) — an in-silico prediction, not a clinical call.

POLE p.Pro677Leu

c.2030C>T · rs2135976402 · VCV2631814

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Conditions

POLE-related disorder

Computational evidence

Protein change
AlphaMissense	0.3843	ambiguous
REVEL	0.451	indeterminate
SaProt	LLR -7.17	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	28.7	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 0.000171% European (non-Finnish) · 2/1,166,358 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,591,302 alleles · very rare exomes 2/1,439,000 · genomes 0/152,302 · 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.Pro677Leu
Coding: c.2030C>T
MANE Select: NM_006231
dbSNP: rs2135976402
Type: single nucleotide variant
Location: chr12:132668499 (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

POLE-related disorder

Similar variants

POLE p.Pro677Thr Uncertain significance ★★ ⚠ same residue
POLE c.3276-1G>C Likely pathogenic ★★ same condition
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same condition
POLE p.Arg1160His Uncertain significance ★★ ⚠ same condition
POLE p.Glu1253Lys Uncertain significance ★★ ⚠ same condition
POLE p.Lys1928Glu Uncertain significance ★★ ⚠ same condition
POLE p.Pro331Ser Uncertain significance ★★ ⚠ same condition
POLE p.Ser117Leu 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-pro677leu (accessed [today's date]).

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