Is TLR3 p.Phe459= (c.1377C>T) pathogenic?

TLR3 p.Phe459= (c.1377C>T) is classified Benign in TLR3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 35.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with herpes simplex encephalitis, susceptibility to, 1.

What condition is associated with TLR3 p.Phe459= (c.1377C>T)?

TLR3 p.Phe459= (c.1377C>T) is associated with herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

TLR3 p.Phe459=

Q: How common is TLR3 p.Phe459= (c.1377C>T) in the general population?

TLR3 p.Phe459= (c.1377C>T) is common (popmax 35.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1377C>T · rs3775290 · VCV403543

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 35.4%, eas) — too common for a highly-penetrant pathogenic allele

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.3	GERP -0.48
Overall
CADD	7.869	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.4% East Asian · 15,865/44,856 alleles

Filtering AF 34.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.7%

Overall 30.2% 487,359/1,613,800 alleles · common exomes 445,532/1,461,816 · genomes 41,827/151,984 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	37.8%	3
East Asiangrpmax	35.4%	3
Admixed American	33.2%	3
South Asian	32.1%	3
European (non-Finnish)	30.6%	3
Remaining individualsnot grpmax-eligible	30.2%	3
Finnishnot grpmax-eligible	29.1%	3
Middle Eastern	28.4%	4
Ashkenazi Jewishnot grpmax-eligible	23.7%	4
African / African-American	19.8%	5

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe459=
Coding: c.1377C>T
MANE Select: NM_003265
dbSNP: rs3775290
Type: single nucleotide variant
Location: chr4:186083063 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB

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.Phe459Leu Uncertain significance ★ ⚠ same residue
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

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-phe459 (accessed [today's date]).

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