# NM_006068.5(TLR6):c.385T>C (p.Ser129Pro)

https://sugi.bio/variant/tlr6-p-ser129pro

## Summary

**TLR6 p.Ser129Pro (c.385T>C)** is classified **Uncertain significance** in TLR6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.844); Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1727700561 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the TLR6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [TLR6](https://sugi.bio/atlas/gene/TLR6/) |
| Protein change (HGVS p.) | p.Ser129Pro |
| Coding change (HGVS c.) | c.385T>C |
| MANE Select transcript | [NM_006068](https://www.ncbi.nlm.nih.gov/nuccore/NM_006068) |
| dbSNP | [rs1727700561](https://www.ncbi.nlm.nih.gov/snp/rs1727700561/) |
| Variant type | single nucleotide variant |
| Location | chr4:38829089-38829089 (GRCh38) |
| ClinVar | [VCV3178055](https://www.ncbi.nlm.nih.gov/clinvar/variation/3178055/) |

**All HGVS expressions:** `NC_000004.11:g.38830710A>G`, `NC_000004.12:g.38829089A>G`, `NG_028087.1:g.32729T>C`, `NG_028087.2:g.44301T>C`, `NM_001394553.1:c.385T>C`, `NM_006068.5:c.385T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.844)
- REVEL 0.595 (indeterminate)
- SaProt LLR -14.447 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 9.344, GERP 2.74, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in TLR6 (of 4,694 modeled).
- CADD: **PHRED 26.2**. 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.*
- 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 **0.00167%** (amr) · 1/60,010 in the highest group · 2/1,614,080 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,010 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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}

**TLR6** population constraint: LOEUF 0.985, pLI 0.00017084, missense-Z 2.0615. *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 85.76, 51% of residues very-high.

**1 experimental structure(s)** (PDB): [4OM7](https://www.rcsb.org/structure/4OM7).

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

*Describes the biological roles of TLR6 (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:** TLR6's established molecular role includes signaling receptor binding. In Reactome, TLR6 is annotated in disease pathway(s) including **IRAK4 deficiency (TLR2/4)**, **MyD88 deficiency (TLR2/4)**.

**Disease mechanism (Reactome):** TLR6 loss or alteration is curated in [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041), [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498), [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110).

### Pathways affected {#pathways}

TLR6 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041) | curated |
| ⚕ [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [Regulation of TLR by endogenous ligand](https://reactome.org/content/detail/R-HSA-5686938) | curated |
| [Toll Like Receptor TLR6:TLR2 Cascade](https://reactome.org/content/detail/R-HSA-168188) | curated |

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

**Molecular function:** signaling receptor binding, Toll-like receptor 2 binding, identical protein binding, protein heterodimerization activity.

**Biological process:** MyD88-dependent toll-like receptor signaling pathway, negative regulation of interleukin-8 production, negative regulation of toll-like receptor 2 signaling pathway, toll-like receptor TLR6:TLR2 signaling pathway, detection of diacyl bacterial lipopeptide, positive regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-22 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TLR6 variant pages (same residue, condition, or type): [TLR6 p.Gly592Val](/variant/tlr6-p-gly592val), [TLR6 p.Thr287=](/variant/tlr6-p-thr287), [TLR6 p.Val465Ile](/variant/tlr6-p-val465ile), [TLR6 p.Ala155Val](/variant/tlr6-p-ala155val), [TLR6 p.Ala35Ser](/variant/tlr6-p-ala35ser), [TLR6 p.Ala644Asp](/variant/tlr6-p-ala644asp), [TLR6 p.Ala65Thr](/variant/tlr6-p-ala65thr), [TLR6 p.Arg293Cys](/variant/tlr6-p-arg293cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3178055). 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.*