Is POLE p.Thr41= (c.123G>A) pathogenic?

POLE p.Thr41= (c.123G>A) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.44%, eas); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Thr41= (c.123G>A)?

POLE p.Thr41= (c.123G>A) is associated with familial colorectal cancer type X, hereditary neoplastic syndrome, Polymerase proofreading-related adenomatous polyposis (ClinVar).

How common is POLE p.Thr41= (c.123G>A) in the general population?

POLE p.Thr41= (c.123G>A) is low-frequency (popmax 1.44%, eas) (gnomAD).

How is Familial colorectal cancer Type X inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLE p.Thr41=

c.123G>A · rs5744734 · VCV240383

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.44%, eas)

Conditions

familial colorectal cancer type X

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.1
Overall
CADD	1.597	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.44% East Asian · 646/44,884 alleles

Filtering AF 1.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.31%

Overall 0.0943% 1,522/1,614,200 alleles · low-frequency exomes 1,065/1,461,876 · genomes 457/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.44%	69
African / African-American	1.02%	98
Remaining individualsnot grpmax-eligible	0.096%	1,042
Admixed American	0.0683%	1,464
South Asian	0.0022%	45,540
European (non-Finnish)	0.000847%	118,003

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.Thr41=
Coding: c.123G>A
MANE Select: NM_006231
dbSNP: rs5744734
Type: single nucleotide variant
Location: chr12:132681219 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 41: an α-helix

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

Disease context

familial colorectal cancer type X — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome Polymerase proofreading-related adenomatous polyposis

For Familial colorectal cancer Type X (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

POLE p.Thr41Arg Uncertain significance ★★ ⚠ same residue
POLE p.Thr41Lys Uncertain significance ★★ ⚠ same residue
POLE p.Thr41Met Uncertain significance ★★ ⚠ same residue
POLE p.Thr41Ser Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely 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

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-thr41 (accessed [today's date]).

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