# NM_007118.4(TRIO):c.5953del (p.Val1985fs)

https://sugi.bio/variant/trio-p-val1985fs

## Summary

**TRIO p.Val1985fs (c.5953del)** is classified **Likely pathogenic** in TRIO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). Associated with micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TRIO gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome.

*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/0017850/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRIO](https://sugi.bio/atlas/gene/TRIO/) |
| Protein change (HGVS p.) | p.Val1985fs |
| Coding change (HGVS c.) | c.5953del |
| MANE Select transcript | [NM_007118](https://www.ncbi.nlm.nih.gov/nuccore/NM_007118) |
| Variant type | Deletion |
| Location | chr5:14472632-14472632 (GRCh38) |
| ClinVar | [VCV4854910](https://www.ncbi.nlm.nih.gov/clinvar/variation/4854910/) |

**All HGVS expressions:** `NC_000005.10:g.14472632del`, `NC_000005.9:g.14472741del`, `NG_052962.1:g.333931del`, `NM_007118.4:c.5953del`, `NR_134469.2:n.6337del`

## 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 -4.626, GERP -3.58 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.217, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 39 of 57**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**TRIO** population constraint: LOEUF 0.217, pLI 1, missense-Z 4.6931; ClinGen dosage — haploinsufficiency 3/3, 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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **1985** lies in an α-helix; a UniProt-annotated variant site (in mrd44); the dh 2 domain.

**4 experimental structure(s)** (PDB): [1NTY](https://www.rcsb.org/structure/1NTY), [2NZ8](https://www.rcsb.org/structure/2NZ8), [6D8Z](https://www.rcsb.org/structure/6D8Z), [7SJ4](https://www.rcsb.org/structure/7SJ4).

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

*Describes the biological roles of TRIO (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}

TRIO participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [NRAGE signals death through JNK](https://reactome.org/content/detail/R-HSA-193648) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |

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

**Biological process:** neuron projection morphogenesis, postsynaptic modulation of chemical synaptic transmission.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-25 |

## Associated conditions {#conditions}

[micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome](https://sugi.bio/atlas/disease/micrognathia-recurrent-infections-behavioral-abnormalities-mild-intellectual-disability-syndrome/).

**Reported phenotype names (ClinVar):** Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY, TRIO-Related Intellectual Disability.

## Similar variants {#similar}

Related TRIO variant pages (same residue, condition, or type): [TRIO c.3332-1_3332del](/variant/trio-c-3332-minus-1-3332del), [TRIO p.Trp2486_Pro2490delinsSer](/variant/trio-p-trp2486-pro2490delinsser), [TRIO c.5491_5496+12del](/variant/trio-c-5491-5496-plus-12del), [TRIO p.Arg100fs](/variant/trio-p-arg100fs), [TRIO p.Arg1897fs](/variant/trio-p-arg1897fs), [TRIO p.Arg2335fs](/variant/trio-p-arg2335fs), [TRIO p.Asp2524fs](/variant/trio-p-asp2524fs), [TRIO p.Glu1924fs](/variant/trio-p-glu1924fs).

### 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 4854910). 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.*