# NM_015650.4(TRAF3IP1):c.373G>A (p.Val125Met)

https://sugi.bio/variant/traf3ip1-p-val125met

## Summary

**TRAF3IP1 p.Val125Met (c.373G>A)** is classified **Pathogenic** in TRAF3IP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-09-06). AlphaMissense: likely pathogenic (0.8202); Very rare (popmax 6.2e-05%); Associated with Senior-Loken syndrome 9.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs886037898 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the TRAF3IP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Senior-Loken syndrome 9.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | TRAF3IP1 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Senior-Loken syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Visual impairment — Very frequent (99-80%)
- Retinal dystrophy — Very frequent (99-80%)
- Hypertension — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Stage 5 chronic kidney disease — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Chronic kidney disease — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016145/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRAF3IP1](https://sugi.bio/atlas/gene/TRAF3IP1/) |
| Protein change (HGVS p.) | p.Val125Met |
| Coding change (HGVS c.) | c.373G>A |
| MANE Select transcript | [NM_015650](https://www.ncbi.nlm.nih.gov/nuccore/NM_015650) |
| dbSNP | [rs886037898](https://www.ncbi.nlm.nih.gov/snp/rs886037898/) |
| Variant type | single nucleotide variant |
| Location | chr2:238328704-238328704 (GRCh38) |
| ClinVar | [VCV254149](https://www.ncbi.nlm.nih.gov/clinvar/variation/254149/) |

**All HGVS expressions:** `NC_000002.11:g.239237345G>A`, `NC_000002.12:g.238328704G>A`, `NG_053055.1:g.13216G>A`, `NM_001139490.1:c.373G>A`, `NM_015650.4:c.373G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8202) — concordant with the pathogenic call
- REVEL 0.445 (indeterminate)
- SaProt LLR -13.206 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.478, GERP 1.08, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.4**. 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 0.94** across the covering region of the MANE Select transcript (238,320,663–238,397,633), spanning 76,970 bp. Chi-square p 0.082. 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): global (via dbSNP) **6.2e-05%** · 1/1,613,918 alleles overall — very rare (popmax 6.2e-05%).

*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}

**TRAF3IP1** population constraint: LOEUF 0.723, pLI 4.227e-08, missense-Z 0.61972. *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):

- **ciliopathy** — Definitive (AR)

## Protein context {#protein}

Residue **125** lies in the 'abolishes microtubules-binding when missing' region; a UniProt-annotated variant site (in slsn9; results in altered folding of the n-terminus; does not affect interaction with ift20; loss of interaction with map4); a UniProt-annotated variant site (in slsn9; results in altered folding of the n-terminus; does not localize to the ciliary tip and transition zone; does not affect interaction with ift20; loss of interaction with map4); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 61.95, 32% of residues very-high.

**2 experimental structure(s)** (PDB): [2EQO](https://www.rcsb.org/structure/2EQO), [8KCQ](https://www.rcsb.org/structure/8KCQ).

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

*Describes the biological roles of TRAF3IP1 (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.*


### Pathways affected {#pathways}

TRAF3IP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | electronic |

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

**Biological process:** morphogenesis of a polarized epithelium, kidney development, negative regulation of protein phosphorylation, negative regulation of protein-containing complex assembly, negative regulation of type I interferon production, negative regulation of defense response to virus.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-09-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-09-06 |

## Associated conditions {#conditions}

[Senior-Loken syndrome 9](https://sugi.bio/atlas/disease/senior-loken-syndrome-9/).

**Reported phenotype names (ClinVar):** Senior-Loken syndrome 9.

## Similar variants {#similar}

Related TRAF3IP1 variant pages (same residue, condition, or type): [TRAF3IP1 p.Val125Ala](/variant/traf3ip1-p-val125ala), [IFT54 p.Arg565Ter](/variant/ift54-p-arg565ter), [IFT54 p.Gly355Glu](/variant/ift54-p-gly355glu), [IFT54 p.Pro30Ser](/variant/ift54-p-pro30ser), [TRAF3IP1 p.Arg271Gln](/variant/traf3ip1-p-arg271gln), [TRAF3IP1 p.Arg271Trp](/variant/traf3ip1-p-arg271trp), [TRAF3IP1 p.Arg470Trp](/variant/traf3ip1-p-arg470trp), [TRAF3IP1 p.Glu229Lys](/variant/traf3ip1-p-glu229lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 254149). 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.*