Is TLR3 p.Pro46= (c.138C>T) pathogenic?

TLR3 p.Pro46= (c.138C>T) is classified Likely benign in TLR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). Ultra-rare (popmax 0.029%, eas); Associated with herpes simplex encephalitis, susceptibility to, 1.

What condition is associated with TLR3 p.Pro46= (c.138C>T)?

TLR3 p.Pro46= (c.138C>T) is associated with herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

How common is TLR3 p.Pro46= (c.138C>T) in the general population?

TLR3 p.Pro46= (c.138C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

TLR3 p.Pro46=

c.138C>T · rs267600111 · VCV2160918

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Conditions

herpes simplex encephalitis, susceptibility to, 1

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 -9.7	GERP -4.1
Overall
CADD	0.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,884 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00211% 34/1,613,924 alleles · ultra-rare exomes 32/1,461,890 · genomes 2/152,034 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,453
South Asian	0.00439%	22,767
European (non-Finnish)	0.00144%	69,413

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: TLR3
Protein: p.Pro46=
Coding: c.138C>T
MANE Select: NM_003265
dbSNP: rs267600111
Type: single nucleotide variant
Location: chr4:186076757 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB
Residue 46: the lrrnt domain

Full TLR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

herpes simplex encephalitis, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TLR3 p.Ala185Val Uncertain significance ★★ ⚠ same condition
TLR3 p.Ala549Thr Uncertain significance ★★ ⚠ same condition
TLR3 p.Ala795Val Uncertain significance ★★ ⚠ same condition
TLR3 p.Ala839Asp Uncertain significance ★★ ⚠ same condition
TLR3 p.Arg331Gln Uncertain significance ★★ ⚠ same condition
TLR3 p.Arg331Trp Uncertain significance ★★ ⚠ same condition
TLR3 p.Arg809Lys Uncertain significance ★★ ⚠ same condition
TLR3 p.Arg885Gln 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/tlr3-p-pro46 (accessed [today's date]).

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