# NM_145725.3(TRAF3):c.1458del (p.Pro487fs)

https://sugi.bio/variant/traf3-p-pro487fs

## Summary

**TRAF3 p.Pro487fs (c.1458del)** is classified **Pathogenic** in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). No gnomAD frequency available for this variant; Associated with TRAF3 haploinsufficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2542634545 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TRAF3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to TRAF3 haploinsufficiency.

*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 | [TRAF3](https://sugi.bio/atlas/gene/TRAF3/) |
| Protein change (HGVS p.) | p.Pro487fs |
| Coding change (HGVS c.) | c.1458del |
| MANE Select transcript | [NM_145725](https://www.ncbi.nlm.nih.gov/nuccore/NM_145725) |
| dbSNP | [rs2542634545](https://www.ncbi.nlm.nih.gov/snp/rs2542634545/) |
| Variant type | Deletion |
| Location | chr14:102905534-102905534 (GRCh38) |
| ClinVar | [VCV2445226](https://www.ncbi.nlm.nih.gov/clinvar/variation/2445226/) |

**All HGVS expressions:** `LRG_229:g.133057del`, `LRG_229t1:c.1458del`, `NC_000014.8:g.103371872del`, `NC_000014.9:g.102905535del`, `NG_027973.1:g.133057del`, `NM_001199427.2:c.1209del`, `NM_001385142.1:c.1317del`, `NM_001385143.1:c.1377del`, `NM_003300.4:c.1458del`, `NM_145725.3:c.1457delT`, `NM_145725.3:c.1458del`, `NM_145726.3:c.1383del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.054, GERP 2.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.321, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (12 of 12)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**TRAF3** population constraint: LOEUF 0.321, pLI 1, missense-Z 4.4189. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **TRAF3 haploinsufficiency** — Moderate (AD)

## Protein context {#protein}

Residue **487** lies in the math domain; a UniProt-annotated variant site (in imd132b; likely pathogenic; decreased traf3 mrna and protein levels and absence of a truncated traf3 protein in patient cells); a UniProt-annotated variant site (in imd132b; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 88.26, 72% of residues very-high.

**10 experimental structure(s)** (PDB): [1FLK](https://www.rcsb.org/structure/1FLK), [1FLL](https://www.rcsb.org/structure/1FLL), [1KZZ](https://www.rcsb.org/structure/1KZZ), [1L0A](https://www.rcsb.org/structure/1L0A), [1RF3](https://www.rcsb.org/structure/1RF3), [1ZMS](https://www.rcsb.org/structure/1ZMS).

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

*Describes the biological roles of TRAF3 (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:** TRAF3's established molecular role includes ubiquitin-protein transferase activity. p.Pro487fs falls in the math domain. In Reactome, TRAF3 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):** TRAF3 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), [TRAF3 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602571).

### Pathways affected {#pathways}

TRAF3 participates in **12 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 |
| ⚕ [TRAF3 deficiency - HSE](https://reactome.org/content/detail/R-HSA-5602571) | curated |
| [Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)](https://reactome.org/content/detail/R-HSA-936964) | curated |
| [Negative regulators of DDX58/IFIH1 signaling](https://reactome.org/content/detail/R-HSA-936440) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 ](https://reactome.org/content/detail/R-HSA-9824878) | curated |
| [Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation](https://reactome.org/content/detail/R-HSA-9828211) | curated |
| [TICAM1-dependent activation of IRF3/IRF7](https://reactome.org/content/detail/R-HSA-9013973) | curated |
| [TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5676594) | curated |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | curated |
| [TRAF3-dependent IRF activation pathway](https://reactome.org/content/detail/R-HSA-918233) | curated |

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

**Molecular function:** ubiquitin-protein transferase activity, tumor necrosis factor receptor binding, protein phosphatase binding, ubiquitin protein ligase binding, thioesterase binding, identical protein binding.

**Biological process:** toll-like receptor signaling pathway, regulation of proteolysis, positive regulation of type I interferon production, tumor necrosis factor-mediated signaling pathway, toll-like receptor 4 signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-14.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development | Pathogenic | criteria provided, single submitter | research | 2023-02-14 |

## Associated conditions {#conditions}

[TRAF3 haploinsufficiency](https://sugi.bio/atlas/disease/traf3-haploinsufficiency/).

**Reported phenotype names (ClinVar):** TRAF3 haploinsufficiency.

## Similar variants {#similar}

Related TRAF3 variant pages (same residue, condition, or type): [TRAF3 c.1136-17del](/variant/traf3-c-1136-minus-17del), [TRAF3 c.297+19del](/variant/traf3-c-297-plus-19del), [TRAF3 p.Lys467fs](/variant/traf3-p-lys467fs), [TRAF3 c.297+6del](/variant/traf3-c-297-plus-6del), [TRAF3 p.Lys171fs](/variant/traf3-p-lys171fs), [TRAF3 p.Lys286fs](/variant/traf3-p-lys286fs), [TRAF3 c.245+10_245+21del](/variant/traf3-c-245-plus-10-245-plus-21del), [TRAF3 c.245+22_245+33del](/variant/traf3-c-245-plus-22-245-plus-33del).

### 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 2445226). 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.*