Is TLR3 p.Pro554Ser (c.1660C>T) pathogenic?

TLR3 p.Pro554Ser (c.1660C>T) is classified Uncertain significance in TLR3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-27). AlphaMissense: ambiguous (0.3633); Ultra-rare (popmax 0.0623%, nfe); Associated with immunodeficiency 83, susceptibility to viral infections.

What condition is associated with TLR3 p.Pro554Ser (c.1660C>T)?

TLR3 p.Pro554Ser (c.1660C>T) is associated with immunodeficiency 83, susceptibility to viral infections, susceptibility to HIV infection, herpes simplex encephalitis, susceptibility to, 1 (ClinVar).

How common is TLR3 p.Pro554Ser (c.1660C>T) in the general population?

TLR3 p.Pro554Ser (c.1660C>T) is ultra-rare (popmax 0.0623%, nfe) (gnomAD).

What do computational predictors say about TLR3 p.Pro554Ser (c.1660C>T)?

AlphaMissense predicts ambiguous (score 0.3633) — an in-silico prediction, not a clinical call.

TLR3 p.Pro554Ser

c.1660C>T · rs121434431 · VCV6662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0623%, nfe)

Conditions

immunodeficiency 83, susceptibility to viral infections

Computational evidence

Protein change
AlphaMissense	0.3633	ambiguous
REVEL	0.583	indeterminate
SaProt	LLR -9.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.95, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,280 bp · p 0.11 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0623% European (non-Finnish) · 735/1,180,056 alleles

Filtering AF 0.0585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.057%

Overall 0.0511% 825/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0623%	1,606
Finnishnot grpmax-eligible	0.0531%	1,883
Remaining individualsnot grpmax-eligible	0.032%	3,124
South Asian	0.0231%	4,337
Middle Eastern	0.0164%	6,084
Admixed American	0.0117%	8,571
African / African-American	0.00934%	10,702

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.Pro554Ser
Coding: c.1660C>T
MANE Select: NM_003265
dbSNP: rs121434431
Type: single nucleotide variant
Location: chr4:186083346 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 20 PDB
Residue 554: a UniProt-annotated variant site (in imd83; causes tlr3 deficiency and predisposition to herpes simplex encephalitis; 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: susceptibility to HIV infection herpes simplex encephalitis, susceptibility to, 1

Similar variants

TLR3 p.Pro554His 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-pro554ser (accessed [today's date]).

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