Is POLE p.Ala1735Ser (c.5203G>T) pathogenic?

POLE p.Ala1735Ser (c.5203G>T) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-17). AlphaMissense: likely benign (0.2724); No allele count reported in gnomAD v4.1 (AN 1,601,856).

How common is POLE p.Ala1735Ser (c.5203G>T) in the general population?

POLE p.Ala1735Ser (c.5203G>T) is no allele count reported in gnomAD v4.1 (AN 1,601,856) (gnomAD).

What do computational predictors say about POLE p.Ala1735Ser (c.5203G>T)?

AlphaMissense predicts likely benign (score 0.2724) — an in-silico prediction, not a clinical call.

POLE p.Ala1735Ser

c.5203G>T · rs2042150896 · VCV967147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2724 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,601,856)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2724	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	28.5	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

No allele count reported in gnomAD v4.1 (AN 1,601,856). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Ala1735Ser
Coding: c.5203G>T
MANE Select: NM_006231
dbSNP: rs2042150896
Type: single nucleotide variant
Location: chr12:132641822 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1735: an α-helix; 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.Ala1735Asp Uncertain significance ★★ ⚠ same residue
POLE p.Ala1735Thr Uncertain significance ★★ same residue
POLE p.Ala1735Val Uncertain significance ★ same residue
POLE p.Ala1735= 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

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-ala1735ser (accessed [today's date]).

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