Is TLR3 p.Ser776= (c.2328A>G) pathogenic?

TLR3 p.Ser776= (c.2328A>G) is classified Likely benign in TLR3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-14). Ultra-rare (popmax 0.052%, afr); Associated with herpes simplex encephalitis, susceptibility to, 1.

What condition is associated with TLR3 p.Ser776= (c.2328A>G)?

TLR3 p.Ser776= (c.2328A>G) is associated with herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

How common is TLR3 p.Ser776= (c.2328A>G) in the general population?

TLR3 p.Ser776= (c.2328A>G) is ultra-rare (popmax 0.052%, afr) (gnomAD).

TLR3 p.Ser776=

c.2328A>G · rs370090850 · VCV1573088

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.052%, afr)

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 -2.2	GERP -3.8
Overall
CADD	0.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.052% African / African-American · 39/75,052 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0345%

Overall 0.00279% 45/1,614,176 alleles · ultra-rare exomes 15/1,461,862 · genomes 30/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.052%	1,924
Middle Eastern	0.033%	3,031
East Asian	0.00223%	44,874
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,180,036

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.Ser776=
Coding: c.2328A>G
MANE Select: NM_003265
dbSNP: rs370090850
Type: single nucleotide variant
Location: chr4:186084014 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB
Residue 776: the tir domain; a UniProt-annotated variant site (inhibition of ifnl1 induction)

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-ser776 (accessed [today's date]).

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