# NM_004620.4(TRAF6):c.856T>C (p.Ser286Pro)

https://sugi.bio/variant/traf6-p-ser286pro

## Summary

**TRAF6 p.Ser286Pro (c.856T>C)** is classified **Uncertain significance** in TRAF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.0145%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs147645716 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0145%, nfe)

## For patients & families {#patients}

This is a change in the TRAF6 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 | [TRAF6](https://sugi.bio/atlas/gene/TRAF6/) |
| Protein change (HGVS p.) | p.Ser286Pro |
| Coding change (HGVS c.) | c.856T>C |
| MANE Select transcript | [NM_004620](https://www.ncbi.nlm.nih.gov/nuccore/NM_004620) |
| dbSNP | [rs147645716](https://www.ncbi.nlm.nih.gov/snp/rs147645716/) |
| Variant type | single nucleotide variant |
| Location | chr11:36490551-36490551 (GRCh38) |
| ClinVar | [VCV2382318](https://www.ncbi.nlm.nih.gov/clinvar/variation/2382318/) |

**All HGVS expressions:** `NC_000011.10:g.36490551A>G`, `NC_000011.9:g.36512101A>G`, `NM_004620.4:c.856T>C`, `NM_145803.3:c.856T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0797)
- REVEL 0.01 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.209 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.327, GERP -3.38, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.063**. 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 0.70** across the covering region of the MANE Select transcript (36,490,295–36,501,245), spanning 10,950 bp. Chi-square p 2.5e-08. 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 **0.0145%** (nfe) · FAF95 0.0127% · FAF99 0.012% · 171/1,180,044 in the highest group · 178/1,614,060 alleles overall — ultra-rare (popmax 0.0145%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0145% | 6,901 |
| African / African-American | 0.00534% | 18,732 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,242 |
| Admixed American | 0.00167% | 60,002 |

*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}

**TRAF6** population constraint: LOEUF 0.356, pLI 0.99997, missense-Z 4.0264. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **286** lies in the 'interaction with tax1bp1' region.

AlphaFold model confidence (whole protein): pLDDT 85.30, 72% of residues very-high.

**13 experimental structure(s)** (PDB): [1LB4](https://www.rcsb.org/structure/1LB4), [1LB5](https://www.rcsb.org/structure/1LB5), [1LB6](https://www.rcsb.org/structure/1LB6), [2ECI](https://www.rcsb.org/structure/2ECI), [2JMD](https://www.rcsb.org/structure/2JMD), [3HCS](https://www.rcsb.org/structure/3HCS).

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

*Describes the biological roles of TRAF6 (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:** TRAF6's established molecular role includes ubiquitin-protein transferase activity. p.Ser286Pro falls in the interaction with tax1bp1 region. In Reactome, TRAF6 is annotated in disease pathway(s) including **SARS-CoV-1 activates/modulates innate immune responses**, **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** TRAF6 loss or alteration is curated in [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

TRAF6 participates in **35 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Alpha-protein kinase 1 signaling pathway](https://reactome.org/content/detail/R-HSA-9645460) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [IKK complex recruitment mediated by RIP1](https://reactome.org/content/detail/R-HSA-937041) | curated |
| [IRAK1 recruits IKK complex](https://reactome.org/content/detail/R-HSA-937039) | curated |
| [IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975144) | curated |
| [IRAK2 mediated activation of TAK1 complex](https://reactome.org/content/detail/R-HSA-937042) | curated |
| [IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975163) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [JNK (c-Jun kinases) phosphorylation and  activation mediated by activated human TAK1](https://reactome.org/content/detail/R-HSA-450321) | curated |
| [MyD88 cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-975871) | curated |
| [MyD88 dependent cascade initiated on endosome](https://reactome.org/content/detail/R-HSA-975155) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [NF-kB is activated and signals survival](https://reactome.org/content/detail/R-HSA-209560) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Regulated proteolysis of p75NTR](https://reactome.org/content/detail/R-HSA-193692) | curated |
| [Regulation of NF-kappa B signaling](https://reactome.org/content/detail/R-HSA-9758274) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | 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 |
| [TRAF6 mediated IRF7 activation](https://reactome.org/content/detail/R-HSA-933541) | curated |
| [TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling](https://reactome.org/content/detail/R-HSA-975110) | curated |
| [TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation](https://reactome.org/content/detail/R-HSA-975138) | curated |
| [TRAF6-mediated induction of TAK1 complex within TLR4 complex](https://reactome.org/content/detail/R-HSA-937072) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | curated |
| [p75NTR recruits signalling complexes](https://reactome.org/content/detail/R-HSA-209543) | curated |
| [NRIF signals cell death from the nucleus](https://reactome.org/content/detail/R-HSA-205043) | electronic |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | electronic |

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

**Molecular function:** ubiquitin-protein transferase activity, protein-macromolecule adaptor activity, ubiquitin conjugating enzyme binding, ubiquitin-ubiquitin ligase activity, histone deacetylase binding, protein kinase B binding.

**Biological process:** autophagosome assembly, negative regulation of transcription by RNA polymerase II, protein polyubiquitination, positive regulation of T cell cytokine production, cytoplasmic pattern recognition receptor signaling pathway, canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-13.

**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 | 2021-08-13 |

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

## Similar variants {#similar}

Related TRAF6 variant pages (same residue, condition, or type): [TRAF6 p.Ala194Thr](/variant/traf6-p-ala194thr), [TRAF6 p.Arg167His](/variant/traf6-p-arg167his), [TRAF6 p.Arg402His](/variant/traf6-p-arg402his), [TRAF6 p.Asn212Ser](/variant/traf6-p-asn212ser), [TRAF6 p.Asp181Ala](/variant/traf6-p-asp181ala), [TRAF6 p.Glu114Asp](/variant/traf6-p-glu114asp), [TRAF6 p.Glu144Lys](/variant/traf6-p-glu144lys), [TRAF6 p.Glu225Gln](/variant/traf6-p-glu225gln).

### 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 2026-07-14); 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 2382318). 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.*