TIAM2

Chr 6

TIAM Rac1 associated GEF 2

Also known as: STEF, TIAM-2

NCBI Gene: 26230 ENSG00000146426 UniProt: Q8IVF5 OMIM: 604709

TIAM2 encodes a guanine nucleotide exchange factor that activates RAC1 GTPase, mediating extracellular laminin signals essential for neurite growth, neuronal migration in the cerebral cortex, and growth cone advancement in developing neurons. Mutations cause autosomal recessive intellectual disability with seizures and cortical malformations, reflecting the protein's critical role in neuronal development and migration. The gene is highly constrained against loss-of-function variants (LOEUF 0.433), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a guanine nucleotide exchange factor. A highly similar mouse protein specifically activates ras-related C3 botulinum substrate 1, converting this Rho-like guanosine triphosphatase (GTPase) from a guanosine diphosphate-bound inactive state to a guanosine triphosphate-bound active state. The encoded protein may play a role in neural cell development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.43

Clinical Summary— TIAM2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

242 VUS of 306 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.000

Z-score 5.59

OE 0.31 (0.22–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.24Z-score

OE missense 0.89 (0.84–0.94)

851 obs / 959.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.22–0.43)

0≤0.351.4

Missense OE?0.89 (0.84–0.94)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 23 / 75.3Missense obs/exp: 851 / 959.5Syn Z: -1.12

This gene — mechanism propensity

0.6647th %ile

GOF

0.6638th %ile

LOF

0.4332th %ile

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

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

306 submitted variants in ClinVar

ClinVar

Classification Summary

VUS242

Likely Benign22

Benign11

242

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	242	0	0	242
Likely Benign	16	1	5	22
Benign	5	2	4	11
Total	263	3	9	275

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap TIAM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →