Is POLE p.Ser2034Phe (c.6101C>T) pathogenic?

POLE p.Ser2034Phe (c.6101C>T) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-12). AlphaMissense: likely benign (0.189); Very rare (popmax 0.0011%, sas).

How common is POLE p.Ser2034Phe (c.6101C>T) in the general population?

POLE p.Ser2034Phe (c.6101C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about POLE p.Ser2034Phe (c.6101C>T)?

AlphaMissense predicts likely benign (score 0.189) — an in-silico prediction, not a clinical call.

POLE p.Ser2034Phe

c.6101C>T · rs1060500834 · VCV405745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.189	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -8.51	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	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	28.1	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,032 alleles · very rare exomes 1/1,461,754 · genomes 0/152,278 · 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.Ser2034Phe
Coding: c.6101C>T
MANE Select: NM_006231
dbSNP: rs1060500834
Type: single nucleotide variant
Location: chr12:132632699 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2034: a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.Ser2034= Likely benign ★ same residue
POLE p.Ser2034fs Pathogenic ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
POLE p.Leu424Val Pathogenic ★★ same type
POLE p.Pro436Ser Likely pathogenic ★★ ⚠ same type

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-ser2034phe (accessed [today's date]).

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