Is POLE p.Asp185= (c.555C>T) pathogenic?

POLE p.Asp185= (c.555C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0143%, sas); Associated with familial colorectal cancer type X.

What condition is associated with POLE p.Asp185= (c.555C>T)?

POLE p.Asp185= (c.555C>T) is associated with familial colorectal cancer type X, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Asp185= (c.555C>T) in the general population?

POLE p.Asp185= (c.555C>T) is ultra-rare (popmax 0.0143%, sas) (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.Asp185=

c.555C>T · rs763871536 · VCV221120

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

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 -1.9	GERP -3.1
Overall
CADD	5.059	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,074 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00921%

Overall 0.00979% 158/1,613,388 alleles · ultra-rare exomes 152/1,461,230 · genomes 6/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,006
European (non-Finnish)	0.0114%	8,737
Remaining individualsnot grpmax-eligible	0.0096%	10,411
East Asian	0.00669%	14,955
African / African-American	0.00134%	74,890

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.Asp185=
Coding: c.555C>T
MANE Select: NM_006231
dbSNP: rs763871536
Type: single nucleotide variant
Location: chr12:132679520 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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: colorectal cancer, susceptibility to, 12 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.Asp185Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp185Glu Uncertain significance ★ ⚠ same residue
POLE p.Asp185Gly 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
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-asp185 (accessed [today's date]).

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