Is POLE p.Ser1019Arg (c.3057C>A) pathogenic?

POLE p.Ser1019Arg (c.3057C>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-30). AlphaMissense: likely pathogenic (0.9311); Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ser1019Arg (c.3057C>A)?

POLE p.Ser1019Arg (c.3057C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser1019Arg (c.3057C>A) in the general population?

POLE p.Ser1019Arg (c.3057C>A) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about POLE p.Ser1019Arg (c.3057C>A)?

AlphaMissense predicts likely pathogenic (score 0.9311) — an in-silico prediction, not a clinical call.

POLE p.Ser1019Arg

c.3057C>A · rs2138688476 · VCV2091995

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9311	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.6	GERP -0.76, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	22.5	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 0.00111% South Asian · 1/90,260 alleles

Overall 6.22e-05% 1/1,606,896 alleles · very rare exomes 1/1,454,728 · genomes 0/152,168 · 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.Ser1019Arg
Coding: c.3057C>A
MANE Select: NM_006231
dbSNP: rs2138688476
Type: single nucleotide variant
Location: chr12:132660972 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1019: a turn; 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.Ser1019Ile Uncertain significance ★★ ⚠ same residue
POLE p.Ser1019= Likely benign ★★ same residue
POLE p.Ser1019Asn Conflicting classifications of pathogenicity ★ ⚠ 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
POLE c.1106+4A>G 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-ser1019arg (accessed [today's date]).

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