Is POLE p.Asn336Ser (c.1007A>G) pathogenic?

POLE p.Asn336Ser (c.1007A>G) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-03-04). AlphaMissense: likely benign (0.2694); Low-frequency (popmax 2.56%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asn336Ser (c.1007A>G)?

POLE p.Asn336Ser (c.1007A>G) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12, Polymerase proofreading-related adenomatous polyposis (ClinVar).

How common is POLE p.Asn336Ser (c.1007A>G) in the general population?

POLE p.Asn336Ser (c.1007A>G) is low-frequency (popmax 2.56%, afr) (gnomAD).

What do computational predictors say about POLE p.Asn336Ser (c.1007A>G)?

AlphaMissense predicts likely benign (score 0.2694) — an in-silico prediction, not a clinical call.

POLE p.Asn336Ser

c.1007A>G · rs5744760 · VCV240370

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2694 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.56%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2694	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.2	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 2.56% African / African-American · 1,909/74,568 alleles

Filtering AF 2.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.43%

Overall 0.141% 2,269/1,604,600 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.56%	39
Admixed American	0.167%	599
Remaining individualsnot grpmax-eligible	0.166%	603
Middle Eastern	0.133%	754
East Asian	0.0223%	4,485
European (non-Finnish)	0.0113%	8,827
South Asian	0.00888%	11,259

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.Asn336Ser
Coding: c.1007A>G
MANE Select: NM_006231
dbSNP: rs5744760
Type: single nucleotide variant
Location: chr12:132676107 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 336: a UniProt-annotated variant site (in)

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: colorectal cancer, susceptibility to, 12 Polymerase proofreading-related adenomatous polyposis

Similar variants

POLE p.Asn336Lys Uncertain significance ★★ ⚠ same residue
POLE p.Asn336= Benign/Likely benign ★★ same residue
POLE p.Asn336Ile Uncertain significance ★ ⚠ same residue
POLE p.Asn336Thr Uncertain significance ★ ⚠ 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

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-asn336ser (accessed [today's date]).

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