TRIO

Chr 5AD

trio Rho guanine nucleotide exchange factor

Also known as: ARHGEF23, MEBAS, MRD44, MRD63, tgat

NCBI Gene: 7204ENSG00000038382UniProt: O75962OMIM: 601893

This gene encodes a large protein that functions as a GDP to GTP exchange factor. This protein promotes the reorganization of the actin cytoskeleton, thereby playing a role in cell migration and growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 0.142 OMIM phenotypes
Clinical Summary— TRIO
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Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
154 unique Pathogenic / Likely Pathogenic· 956 VUS of 1754 total submissions
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Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TRIO
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?
0.14LOEUF
pLI 1.000
Z-score 10.61
OE 0.09 (0.06–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?
5.32Z-score
OE missense 0.64 (0.61–0.68)
1143 obs / 1772.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?
LoF OE?0.09 (0.06–0.14)
0≤0.351.4
Missense OE?0.64 (0.61–0.68)
0≤0.61.4
Synonymous OE?1.04
0≤1.21.6
LoF obs/exp: 14 / 157.8Missense obs/exp: 1143 / 1772.9Syn Z: -0.92
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongTRIO-related intellectual disabilityOTHERAD

This gene — mechanism propensity

DN
0.4289th %ile
GOF
0.6052th %ile
LOF
0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 81% of P/LP variants are LoF · LOEUF 0.14 · ClinGen HI: Sufficient evidence for dosage pathogenicity
GOF1 literature citation

Literature Evidence

GOFTransfection of the mutations into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect.1
LOFLarge-scale discovery of novel genetic causes of developmental disorders2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 27418539 ↗
  2. 2.PMID 25533962 ↗

ClinVar Variant Classifications

1754 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63
Likely Pathogenic91
VUS956
Likely Benign376
Benign177
Conflicting40
63
Pathogenic
91
Likely Pathogenic
956
VUS
376
Likely Benign
177
Benign
40
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
57
6
0
0
63
Likely Pathogenic
67
20
3
1
91
VUS
15
878
49
14
956
Likely Benign
0
81
133
162
376
Benign
0
7
157
13
177
Conflicting
—40
Total1399923421901,703

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

33 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap TRIO — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TRIO · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Congenital AnomalyPediatric Cancer

Genetic Overlap Between Anomalies and Cancer in Kids in the Children's Oncology Group: The COG GOBACK Study

ACTIVE NOT RECRUITING
NCT05071859Children's Oncology GroupStarted 2021-09-10
Whole Genome SequencingQuestionnaire AdministrationBiospecimen collection
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Neurodevelopmental Disorders and Developmental Abnormalities

Transcriptomic Approach for the Identification and Prioritization of Genome Variants in Neurodevelopmental Disorders With Malformation

RECRUITING
NCT06762678Phase NAUniversity Hospital, AngersStarted 2025-11-04
RNA sequencing and whole genome sequencing in a trio way
Neoplastic Syndromes, HereditaryCancerGenetic Predisposition to Disease

Cancer Predisposition Testing by Family-based Whole-genome Sequencing (WGS) in Every Child With Newly Diagnosed Cancer

RECRUITING
NCT04903782Sydney Children's Hospitals NetworkStarted 2021-03-08
Family-based whole genome sequencing
Rare DiseasesGenetic DiseaseUndiagnosed Disease

UW Undiagnosed Genetic Diseases Program

RECRUITING
NCT04586075University of Wisconsin, MadisonStarted 2021-07-16
Trio Whole Genome Sequencing and Participant-Specific Research
Specific Language and Learning Disorders (SLLD)

Study of the Value of Trio Exome Sequencing in the Etiological Assessment of Specific Non-syndromic Language and Learning Disorders

RECRUITING
NCT05939739Phase NACentre Hospitalier Universitaire DijonStarted 2023-08-07
Blood samplesConsultation for results deliveryStudy Humanities and Social Sciences
Early-stage Breast CancerHormone Receptor Positive Breast CarcinomaInvasive Breast Cancer

Trastuzumab Deruxtecan Alone or in Combination With Anastrozole for the Treatment of Early Stage HER2 Low, Hormone Receptor Positive Breast Cancer

RECRUITING
NCT04553770Phase PHASE2Jonsson Comprehensive Cancer CenterStarted 2020-10-09
AnastrozoleTherapeutic Conventional SurgeryTrastuzumab Deruxtecan
High-Risk CancerLocally Advanced Breast Cancer

Three Fraction Radiation to Induce Immuno-Oncologic Response

ACTIVE NOT RECRUITING
NCT03978663Phase NALondon Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sStarted 2020-09-02
Neoadjuvant radiotherapy
Cerebral Palsy

CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial

RECRUITING
NCT05835674Rigshospitalet, DenmarkStarted 2023-04-01
Early intervention program
Infant, Newborn, DiseaseGenetic Disease

Genome Sequencing in the Intensive Care Unit Population

ENROLLING BY INVITATION
NCT04848090Phase NAJerry Vockley, MD, PhDStarted 2020-07-13
Neonate WGS Testing
Neuromuscular Diseases

The Neuroimage Study of the Neuromuscular Disorders.

RECRUITING
NCT05048862National Taiwan University HospitalStarted 2021-08-01
Neuromuscular ultrasoundMuscle MRINerve conduction studies and autonomic function tests
Heart Defects, Congenital

Genetics of Ventriculo-arterial Discordance

ACTIVE NOT RECRUITING
NCT05330338Phase NANantes University HospitalStarted 2022-09-07
Genetic analyses: whole genome sequencing

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients