Is POLE p.Arg154Ser (c.462G>C) pathogenic?

POLE p.Arg154Ser (c.462G>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 2 submitters; last evaluated 2021-05-27). AlphaMissense: ambiguous (0.4315); Very rare (popmax 0.00167%, amr).

How common is POLE p.Arg154Ser (c.462G>C) in the general population?

POLE p.Arg154Ser (c.462G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about POLE p.Arg154Ser (c.462G>C)?

AlphaMissense predicts ambiguous (score 0.4315) — an in-silico prediction, not a clinical call.

POLE p.Arg154Ser

c.462G>C · rs555774342 · VCV540784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4315	ambiguous
REVEL	0.101	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -3.7, phastCons 0.001
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	12.28	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 0.00167% Admixed American · 1/60,010 alleles

Overall 6.2e-05% 1/1,613,034 alleles · very rare exomes 1/1,460,706 · genomes 0/152,328 · 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.Arg154Ser
Coding: c.462G>C
MANE Select: NM_006231
dbSNP: rs555774342
Type: single nucleotide variant
Location: chr12:132679613 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 154: a β-strand

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

Similar variants

POLE p.Arg154Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg154= Likely benign ★ 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-arg154ser (accessed [today's date]).

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