# NM_003265.3(TLR3):c.448A>T (p.Ile150Phe)

https://sugi.bio/variant/tlr3-p-ile150phe

## Summary

**TLR3 p.Ile150Phe (c.448A>T)** is classified **Uncertain significance** in TLR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely benign (0.1035); Very rare (popmax 0.000509%, nfe); Associated with herpes simplex encephalitis, susceptibility to, 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2099302909 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the TLR3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to herpes simplex encephalitis, susceptibility to, 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TLR3](https://sugi.bio/atlas/gene/TLR3/) |
| Protein change (HGVS p.) | p.Ile150Phe |
| Coding change (HGVS c.) | c.448A>T |
| MANE Select transcript | [NM_003265](https://www.ncbi.nlm.nih.gov/nuccore/NM_003265) |
| dbSNP | [rs2099302909](https://www.ncbi.nlm.nih.gov/snp/rs2099302909/) |
| Variant type | single nucleotide variant |
| Location | chr4:186078846-186078846 (GRCh38) |
| ClinVar | [VCV1004752](https://www.ncbi.nlm.nih.gov/clinvar/variation/1004752/) |

**All HGVS expressions:** `LRG_117:g.14692A>T`, `NC_000004.11:g.187000000A>T`, `NC_000004.12:g.186078846A>T`, `NG_007278.1:g.14692A>T`, `NM_003265.3:c.448A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1035)
- REVEL 0.042 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.374 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.304, GERP -0.758, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.47**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (186,076,620–186,082,546), spanning 5,926 bp. Chi-square p 0.74. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,854 in the highest group · 6/1,613,794 alleles overall — very rare (popmax 0.000509%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TLR3** population constraint: LOEUF 0.796, pLI 1.2954e-08, missense-Z 1.3402. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.64, 74% of residues very-high.

**20 experimental structure(s)** (PDB): [1ZIW](https://www.rcsb.org/structure/1ZIW), [2A0Z](https://www.rcsb.org/structure/2A0Z), [2MK9](https://www.rcsb.org/structure/2MK9), [2MKA](https://www.rcsb.org/structure/2MKA), [3ULU](https://www.rcsb.org/structure/3ULU), [3ULV](https://www.rcsb.org/structure/3ULV).

## What this gene does {#gene-function}

*Describes the biological roles of TLR3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TLR3's established molecular role includes double-stranded RNA binding. In Reactome, TLR3 is annotated in disease pathway(s) including **RSV-host interactions**, **TICAM1 deficiency - HSE**.

**Disease mechanism (Reactome):** TLR3 loss or alteration is curated in [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110), [TICAM1 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602566), [TLR3 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602410).

### Pathways affected {#pathways}

TLR3 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| ⚕ [TICAM1 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602566) | curated |
| ⚕ [TLR3 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602410) | curated |
| ⚕ [TRAF3 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602571) | curated |
| ⚕ [UNC93B1 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602415) | curated |
| [RIP-mediated NFkB activation via ZBP1](https://reactome.org/content/detail/R-HSA-1810476) | curated |
| [Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation](https://reactome.org/content/detail/R-HSA-9828211) | curated |
| [TICAM1, RIP1-mediated IKK complex recruitment](https://reactome.org/content/detail/R-HSA-168927) | curated |
| [TICAM1,TRAF6-dependent induction of TAK1 complex](https://reactome.org/content/detail/R-HSA-9014325) | curated |
| [TICAM1-dependent activation of IRF3/IRF7](https://reactome.org/content/detail/R-HSA-9013973) | curated |
| [TLR3-mediated TICAM1-dependent programmed cell death](https://reactome.org/content/detail/R-HSA-9013957) | curated |
| [Toll Like Receptor 3 (TLR3) Cascade](https://reactome.org/content/detail/R-HSA-168164) | curated |
| [Trafficking and processing of endosomal TLR](https://reactome.org/content/detail/R-HSA-1679131) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** double-stranded RNA binding, transmembrane signaling receptor activity, pattern recognition receptor activity, identical protein binding.

**Biological process:** toll-like receptor signaling pathway, positive regulation of gene expression, positive regulation of chemokine production, positive regulation of interferon-alpha production, positive regulation of interferon-beta production, positive regulation of type II interferon production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-03 |

## Associated conditions {#conditions}

[herpes simplex encephalitis, susceptibility to, 1](https://sugi.bio/atlas/disease/herpes-simplex-encephalitis-susceptibility-to-1/).

**Reported phenotype names (ClinVar):** Herpes simplex encephalitis, susceptibility to, 1, ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED (HERPES-SPECIFIC), SUSCEPTIBILITY TO, 1.

## Similar variants {#similar}

Related TLR3 variant pages (same residue, condition, or type): [TLR3 p.Ile150=](/variant/tlr3-p-ile150), [TLR3 p.Ala185Val](/variant/tlr3-p-ala185val), [TLR3 p.Ala549Thr](/variant/tlr3-p-ala549thr), [TLR3 p.Ala795Val](/variant/tlr3-p-ala795val), [TLR3 p.Ala839Asp](/variant/tlr3-p-ala839asp), [TLR3 p.Arg331Gln](/variant/tlr3-p-arg331gln), [TLR3 p.Arg331Trp](/variant/tlr3-p-arg331trp), [TLR3 p.Arg809Lys](/variant/tlr3-p-arg809lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1004752). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*