TRIO

Chr 5AD

trio Rho guanine nucleotide exchange factor

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

NCBI Gene: 7204 ENSG00000038382 UniProt: O75962 OMIM: 601893

TRIO encodes a guanine nucleotide exchange factor that activates RHOA and RAC1 GTPases to coordinate actin cytoskeleton remodeling essential for cell migration, neurite outgrowth, and synaptic function in developing neurons. Mutations cause autosomal dominant intellectual developmental disorders that can present with either microcephaly or macrocephaly. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.139), indicating that even heterozygous loss significantly impacts neurodevelopment.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 44, with microcephalyMIM #617061

Intellectual developmental disorder, autosomal dominant 63, with macrocephalyMIM #618825

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic intellectual disability · AD · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1091

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in TRIO?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 18

3,547 rare PASS variants

Rare truncating (LoF)

1 in 340

210 rare PASS variants

Rare synonymous (reference)

1 in 23

1,920 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TRIO. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 890
South Asian	~43k	1 in 22	1 in 190
Remaining (unassigned)	~30k	1 in 17	1 in 290
European (Finnish)	~27k	1 in 50	1 in 810
Admixed American	~22k	1 in 21	1 in 340
African / African American	~21k	1 in 18	1 in 660
East Asian	~20k	1 in 23	1 in 950
Ashkenazi Jewish	~13k	1 in 97	1 in 270
Middle Eastern	~2,884	1 in 18	1 in 480

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 53 of 57 coding exons well covered in gnomAD exomes; exons 1, 25, 42, 48 marginal. Genomes: all 57.? see exons ↓