Is POLE p.Ala31Ser (c.91G>T) pathogenic?

POLE p.Ala31Ser (c.91G>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 24 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1299); Low-frequency (popmax 2.42%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala31Ser (c.91G>T)?

POLE p.Ala31Ser (c.91G>T) is associated with hereditary neoplastic syndrome, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Ala31Ser (c.91G>T) in the general population?

POLE p.Ala31Ser (c.91G>T) is low-frequency (popmax 2.42%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ala31Ser (c.91G>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

POLE p.Ala31Ser

c.91G>T · rs34047482 · VCV221182

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 24 submitters

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.42%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -1.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.44, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	14.2	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 2.42% European (non-Finnish) · 28,567/1,180,014 alleles

Filtering AF 2.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.39%

Overall 1.97% 31,848/1,614,170 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.42%	41
Remaining individualsnot grpmax-eligible	1.54%	65
South Asian	1.02%	98
Admixed American	0.841%	119
Finnishnot grpmax-eligible	0.8%	125
Middle Eastern	0.478%	209
African / African-American	0.398%	251
Ashkenazi Jewishnot grpmax-eligible	0.142%	705
East Asian	0.00446%	22,440

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.Ala31Ser
Coding: c.91G>T
MANE Select: NM_006231
dbSNP: rs34047482
Type: single nucleotide variant
Location: chr12:132681251 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 31: a UniProt-annotated variant site (in); an α-helix

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

Also linked: colon carcinoma colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Ala31Val Uncertain significance ★★ ⚠ same residue
POLE p.Ala31= Likely benign ★★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-ala31ser (accessed [today's date]).

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