# NM_001039141.3(TRIOBP):c.2375_2379del (p.Arg792fs)

https://sugi.bio/variant/triobp-p-arg792fs

## Summary

**TRIOBP p.Arg792fs (c.2375_2379del)** is classified **Likely pathogenic** in TRIOBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 28.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the TRIOBP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive nonsyndromic hearing loss 28.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022617/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRIOBP](https://sugi.bio/atlas/gene/TRIOBP/) |
| Protein change (HGVS p.) | p.Arg792fs |
| Coding change (HGVS c.) | c.2375_2379del |
| MANE Select transcript | [NM_001039141](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039141) |
| Variant type | Deletion |
| Location | chr22:37724929-37724933 (GRCh38) |
| ClinVar | [VCV4852230](https://www.ncbi.nlm.nih.gov/clinvar/variation/4852230/) |

**All HGVS expressions:** `NC_000022.10:g.38120938_38120942del`, `NC_000022.11:g.37724931_37724935del`, `NG_012857.1:g.32944_32948del`, `NM_001039141.3:c.2375_2379del`

## 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 -1.174, GERP 1.51 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.865, pLI 5.704e-43. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 21.6**. 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** — 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.
- Repeat context: **simple_repeat** (AACCCCAGAACATCCTGTGCCCAGCGGGACAATCCCAGAGCCTCCTCTCCCAATAGAGCTACACGAGACAACCCCAGAACATCCTGTGCCCAGCGGGACAATCCCAGAGCCTCCAGAACCTCCTCTCCCAATAGAGCCACACGAGAC, AGCCTCCTCTCCCAATAGAGCCACACGAGAGAACCCCAGAACATCCTGTGCCCAGCGGGACAATCCCAGAGACCTCCTCTCCCAATAGAGCCACACGAGACAACCCCAGAACATCCTGTGCCCAGCGGGACAATCCCAGAGCCTCCTCTCCCAATAGAGCTACACGAGACAACCCCAGAACATCCTGTGCCCAGCGGGACAATCCCAGAGCCTCC, CCAGAGCCTCCTCTCCCAACAGAACCATCCAACAAGACAACCCCAGAACATCCTGTGCCCACGGGACAATC). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,986 in the highest group · 3/1,613,790 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,803 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,179,986 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**TRIOBP** population constraint: LOEUF 0.865, pLI 5.704e-43, missense-Z 1.2819; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **hearing loss, autosomal recessive** — Definitive (AR)

## Protein context {#protein}

Residue **792** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 40.77, 10% of residues very-high.

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

*Describes the biological roles of TRIOBP (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:** TRIOBP's established molecular role includes ubiquitin protein ligase binding. p.Arg792fs falls in the disordered region.


### Pathways affected {#pathways}

TRIOBP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | other |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | other |

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

**Molecular function:** ubiquitin protein ligase binding, actin filament binding.

**Biological process:** positive regulation of substrate adhesion-dependent cell spreading.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-23 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 28](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-28/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 28.

## Similar variants {#similar}

Related TRIOBP variant pages (same residue, condition, or type): [TRIOBP p.His1440fs](/variant/triobp-p-his1440fs), [TRIOBP p.Ser578fs](/variant/triobp-p-ser578fs), [TRIOBP p.Ser688_Pro711del](/variant/triobp-p-ser688-pro711del), [TRIOBP p.Gln398del](/variant/triobp-p-gln398del), [TRIOBP p.Ala619fs](/variant/triobp-p-ala619fs), [TRIOBP p.Gln740fs](/variant/triobp-p-gln740fs), [TRIOBP p.Leu1004fs](/variant/triobp-p-leu1004fs), [TRIOBP p.Phe368fs](/variant/triobp-p-phe368fs).

### 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 4852230). 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.*