Is TLR3 p.Phe798fs (c.2394del) pathogenic?

TLR3 p.Phe798fs (c.2394del) is classified Uncertain significance in TLR3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-22). Ultra-rare (popmax 0.0329%, sas); Associated with immunodeficiency 83, susceptibility to viral infections.

What condition is associated with TLR3 p.Phe798fs (c.2394del)?

TLR3 p.Phe798fs (c.2394del) is associated with immunodeficiency 83, susceptibility to viral infections, herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

How common is TLR3 p.Phe798fs (c.2394del) in the general population?

TLR3 p.Phe798fs (c.2394del) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

TLR3 p.Phe798fs

c.2394del · rs757764376 · VCV2153676

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

immunodeficiency 83, susceptibility to viral infections

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.8	GERP 0.94
Overall
CADD	23.0	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 0.0329% South Asian · 30/91,080 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00217% 35/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
European (non-Finnish)	0.000424%	236,007

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.Phe798fs
Coding: c.2394del
MANE Select: NM_003265
dbSNP: rs757764376
Type: Deletion
Location: chr4:186084076 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB
Residue 798: 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

immunodeficiency 83, susceptibility to viral infections — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: herpes simplex encephalitis, susceptibility to, 1

Similar variants

TLR3 p.Phe798= Likely benign ★ same residue
TLR3 c.634-12del Benign/Likely benign ★★ same condition
TLR3 p.Asn196fs Uncertain significance ★ same condition
TLR3 p.Asn901fs Uncertain significance ★ same condition
TLR3 p.Asp36_Thr43del Uncertain significance ★ same condition
TLR3 p.Gln113fs Uncertain significance ★ same condition
TLR3 p.His432_Leu433insTer Uncertain significance ★ same condition
TLR3 p.His563fs 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-phe798fs (accessed [today's date]).

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