Is POLE p.Arg310Ser (c.930G>C) pathogenic?

POLE p.Arg310Ser (c.930G>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.9508); Very rare (popmax 6.2e-05%).

How common is POLE p.Arg310Ser (c.930G>C) in the general population?

POLE p.Arg310Ser (c.930G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about POLE p.Arg310Ser (c.930G>C)?

AlphaMissense predicts likely pathogenic (score 0.9508) — an in-silico prediction, not a clinical call.

POLE p.Arg310Ser

c.930G>C · rs2136014033 · VCV2915930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9508	likely pathogenic
REVEL	0.404	indeterminate
SaProt	LLR -13.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.49	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.42	GERP -0.54, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 6.2e-05%

Overall 6.2e-05% 1/1,613,264 alleles · very rare exomes 1/1,460,916 · genomes 0/152,348 · 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.Arg310Ser
Coding: c.930G>C
MANE Select: NM_006231
dbSNP: rs2136014033
Type: single nucleotide variant
Location: chr12:132676184 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 310: a β-strand

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

Similar variants

POLE p.Arg310Gly Uncertain significance ★★ ⚠ same residue
POLE p.Arg310Met Uncertain significance ★★ ⚠ same residue
POLE p.Arg310fs 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

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-arg310ser (accessed [today's date]).

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