TIGIT

Chr 3

T cell immunoreceptor with Ig and ITIM domains

Also known as: VSIG9, VSTM3, WUCAM

NCBI Gene: 201633 ENSG00000181847 UniProt: Q495A1 OMIM: 612859

TIGIT encodes an inhibitory immune receptor that suppresses T-cell and NK cell activation by binding to ligands PVR/CD155 and NECTIN2/CD112 on antigen-presenting cells, thereby modulating immune responses through inhibition of PI3K, MAPK, and NF-kappa-B signaling pathways. The gene shows low constraint to loss-of-function variation (pLI 0.02, LOEUF 1.05), and no Mendelian diseases have been established from mutations in this gene. TIGIT is primarily studied in the context of cancer immunotherapy and autoimmune diseases rather than pediatric neurogenetic disorders.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the PVR (poliovirus receptor) family of immunoglobin proteins. The product of this gene is expressed on several classes of T cells including follicular B helper T cells (TFH). The protein has been shown to bind PVR with high affinity; this binding is thought to assist interactions between TFH and dendritic cells to regulate T cell dependent B cell responses.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.05

Clinical Summary— TIGIT

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

32 VUS of 48 total submissions

💊

Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.018

Z-score 1.48

OE 0.46 (0.23–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.88–1.16)

143 obs / 141.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.46 (0.23–1.05)

0≤0.351.4

Missense OE?1.01 (0.88–1.16)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 4 / 8.7Missense obs/exp: 143 / 141.6Syn Z: 0.61

This gene — mechanism propensity

0.83top 10%

GOF

0.77top 25%

LOF

0.1697th %ile

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

DNprediction above median

GOFprediction 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

48 submitted variants in ClinVar

ClinVar

Classification Summary

VUS32

Likely Benign9

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	32	0	32
Likely Benign	8	1	9
Benign	0	0	0
Total	40	1	41

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap TIGIT — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →