# NM_147686.4(TRAF3IP2):c.1674C>A (p.Pro558=)

https://sugi.bio/variant/traf3ip2-p-pro558

## Summary

**TRAF3IP2 p.Pro558= (c.1674C>A)** is classified **Likely benign** in TRAF3IP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Ultra-rare (popmax 0.0666%, amr); Associated with candidiasis, familial, 8.

**At a glance:** Likely benign · review: Single submitter · rsID rs769958417 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0666%, amr)

## For patients & families {#patients}

This is a change in the TRAF3IP2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to candidiasis, familial, 8.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | TRAF3IP2 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Chronic mucocutaneous candidiasis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the mouth — Very frequent (99-80%)
- Abnormal lip morphology — Very frequent (99-80%)
- Abnormality of the skin — Very frequent (99-80%)
- Hyperkeratosis — Very frequent (99-80%)
- Skin rash — Very frequent (99-80%)
- Abnormal fingernail morphology — Very frequent (99-80%)
- Abnormality of the nail — Very frequent (99-80%)
- Broad nail — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015981/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRAF3IP2](https://sugi.bio/atlas/gene/TRAF3IP2/) |
| Protein change (HGVS p.) | p.Pro558= |
| Coding change (HGVS c.) | c.1674C>A |
| MANE Select transcript | [NM_147686](https://www.ncbi.nlm.nih.gov/nuccore/NM_147686) |
| dbSNP | [rs769958417](https://www.ncbi.nlm.nih.gov/snp/rs769958417/) |
| Variant type | single nucleotide variant |
| Location | chr6:111559429-111559429 (GRCh38) |
| ClinVar | [VCV1123268](https://www.ncbi.nlm.nih.gov/clinvar/variation/1123268/) |

**All HGVS expressions:** `LRG_1337:g.51450C>A`, `LRG_1337t1:c.1674C>A`, `NC_000006.11:g.111880632G>T`, `NC_000006.12:g.111559429G>T`, `NG_032030.2:g.51450C>A`, `NM_001164281.3:c.1671C>A`, `NM_001164283.3:c.306C>A`, `NM_147200.3:c.1701C>A`, `NM_147686.4:c.1674C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 0.964, GERP -2.24, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.767**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.26 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0666%** (amr) · FAF95 0.0502% · FAF99 0.0446% · 40/60,016 in the highest group · 40/1,613,840 alleles overall — ultra-rare (popmax 0.0666%, amr).

*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}

**TRAF3IP2** population constraint: LOEUF 0.771, pLI 2.2933e-05, missense-Z 2.1434. *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 53.91, 16% of residues very-high.

**1 experimental structure(s)** (PDB): [9OT1](https://www.rcsb.org/structure/9OT1).

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

*Describes the biological roles of TRAF3IP2 (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:** TRAF3IP2's established molecular role includes ubiquitin protein ligase activity.


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

**Molecular function:** ubiquitin protein ligase activity.

**Biological process:** positive regulation of defense response to virus by host, inflammatory response, interleukin-17A-mediated signaling pathway, positive regulation of canonical NF-kappaB signal transduction, protein K63-linked ubiquitination, interleukin-17-mediated signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

## Associated conditions {#conditions}

[candidiasis, familial, 8](https://sugi.bio/atlas/disease/candidiasis-familial-8/).

**Reported phenotype names (ClinVar):** Candidiasis, familial, 8.

## Similar variants {#similar}

Related TRAF3IP2 variant pages (same residue, condition, or type): [TRAF3IP2 c.1201+1G>C](/variant/traf3ip2-c-1201-plus-1g-c), [TRAF3IP2 p.Ala328Thr](/variant/traf3ip2-p-ala328thr), [TRAF3IP2 p.Ala36Val](/variant/traf3ip2-p-ala36val), [TRAF3IP2 p.Ala473Thr](/variant/traf3ip2-p-ala473thr), [TRAF3IP2 p.Asn45Lys](/variant/traf3ip2-p-asn45lys), [TRAF3IP2 p.Gln18His](/variant/traf3ip2-p-gln18his), [TRAF3IP2 p.Glu479Lys](/variant/traf3ip2-p-glu479lys), [TRAF3IP2 p.Gly353Asp](/variant/traf3ip2-p-gly353asp).

### 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 1123268). 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.*