Is TLR3 p.Phe375Ser (c.1124T>C) pathogenic?

TLR3 p.Phe375Ser (c.1124T>C) is classified Uncertain significance in TLR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). AlphaMissense: likely pathogenic (0.9328); Absent from gnomAD v4.1; Associated with herpes simplex encephalitis, susceptibility to, 1.

What condition is associated with TLR3 p.Phe375Ser (c.1124T>C)?

TLR3 p.Phe375Ser (c.1124T>C) is associated with herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

How common is TLR3 p.Phe375Ser (c.1124T>C) in the general population?

TLR3 p.Phe375Ser (c.1124T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLR3 p.Phe375Ser (c.1124T>C)?

AlphaMissense predicts likely pathogenic (score 0.9328) — an in-silico prediction, not a clinical call.

TLR3 p.Phe375Ser

c.1124T>C · rs2478225658 · VCV1714661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9328 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

herpes simplex encephalitis, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.9328	likely pathogenic · top 5% in TLR3
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -15.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,280 bp · p 0.11 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TLR3
Protein: p.Phe375Ser
Coding: c.1124T>C
MANE Select: NM_003265
dbSNP: rs2478225658
Type: single nucleotide variant
Location: chr4:186082810 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB
Residue 375: a turn

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-phe375ser (accessed [today's date]).

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