Is TLR2 p.Arg447Ter (c.1339C>T) pathogenic?

TLR2 p.Arg447Ter (c.1339C>T) is classified Uncertain significance in TLR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-22). Ultra-rare (popmax 0.0891%, eas); Associated with colorectal cancer.

What condition is associated with TLR2 p.Arg447Ter (c.1339C>T)?

TLR2 p.Arg447Ter (c.1339C>T) is associated with colorectal cancer, leprosy, susceptibility to, 3 (ClinVar).

How common is TLR2 p.Arg447Ter (c.1339C>T) in the general population?

TLR2 p.Arg447Ter (c.1339C>T) is ultra-rare (popmax 0.0891%, eas) (gnomAD).

TLR2 p.Arg447Ter

c.1339C>T · VCV3892656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Conditions

colorectal cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.1, phastCons 0.65
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0891% East Asian · 40/44,880 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.0368% 594/1,614,098 alleles · ultra-rare exomes 552/1,461,866 · genomes 42/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
Middle Eastern	0.066%	1,515
European (non-Finnish)	0.0419%	2,384
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0283%	3,530
African / African-American	0.016%	6,252
Finnishnot grpmax-eligible	0.00469%	21,335
South Asian	0.00329%	30,361

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: TLR2
Protein: p.Arg447Ter
Coding: c.1339C>T
MANE Select: NM_001318789
Type: single nucleotide variant
Location: chr4:153704246 (GRCh38)
Gene constraint: LOEUF 1.432 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 7 PDB

Full TLR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: leprosy, susceptibility to, 3

Similar variants

TLR2 p.Arg447Gln Uncertain significance ★ ⚠ same residue
TLR2 p.Leu542= Benign/Likely benign ★★ same condition
TLR2 p.Cys353Ter Uncertain significance ★ same condition
TLR2 p.Ile91Val Conflicting classifications of pathogenicity ★ ⚠ same condition
TLR2 p.Ser101fs Uncertain significance ★ same condition
TLR2 p.Arg571His Likely benign ★★ same type
TLR2 p.Arg579His Benign ★★ same type
TLR2 p.Gly38= Benign ★★ 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/tlr2-p-arg447ter (accessed [today's date]).

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