TSPAN12

Chr 7AD

tetraspanin 12

Also known as: EVR5, NET-2, NET2, TM4SF12

NCBI Gene: 23554ENSG00000106025UniProt: O95859

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Exudative vitreoretinopathy 5MIM #613310
AD
UniProtVitreoretinopathy, exudative 5
332
ClinVar variants
71
Pathogenic / LP
0.69
pLI score
0
Active trials
Clinical Summary— TSPAN12
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Gene-Disease Validity (ClinGen)
TSPAN12-related exudative vitreoretinopathy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.69) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 155 VUS of 332 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.46LOEUF
pLI 0.695
Z-score 3.14
OE 0.18 (0.08–0.46)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.77Z-score
OE missense 0.83 (0.72–0.96)
131 obs / 158.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.08–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.72–0.96)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 3 / 17.0Missense obs/exp: 131 / 158.2Syn Z: -0.04

ClinVar Variant Classifications

332 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58
Likely Pathogenic13
VUS155
Likely Benign67
Benign28
Conflicting11
58
Pathogenic
13
Likely Pathogenic
155
VUS
67
Likely Benign
28
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
5
32
0
58
Likely Pathogenic
7
3
3
0
13
VUS
2
113
39
1
155
Likely Benign
1
1
26
39
67
Benign
0
2
24
2
28
Conflicting
—11
Total3112412442332

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

View in ClinVar →

Protein Context — Lollipop Plot

TSPAN12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TSPAN12-related exudative vitreoretinopathy

definitive
ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Eye
G2P ↗
splice region variantsplice acceptor variantframeshift variantstop gainedmissense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TETRASPANIN 12; TSPAN12
MIM #613138 · *

Exudative vitreoretinopathy 5

MIM #613310

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ocular Features and Mutation Spectrum of Patients With Familial Exudative Vitreoretinopathy.
Tao T et al.·Invest Ophthalmol Vis Sci
2021Cohort
Phenotyping and genotyping FEVR: Molecular genetics, clinical and imaging features, and therapeutics.
Wang Y et al.·Prog Retin Eye Res
2025Review
Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome.
Le V et al.·Cells
2023Review
Novel Exon 7 Deletions in TSPAN12 in a Three-Generation FEVR Family: A Case Report and Literature Review.
Jiang Z et al.·Genes (Basel)
2023Review
Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell-Fibroblast Crosstalk.
Shoda T et al.·Gastroenterology
2022
Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy.
Ju Y et al.·Hum Genomics
2024
Genetic Characteristics and Clinical Manifestations of Foveal Hypoplasia in Familial Exudative Vitreoretinopathy.
Ju Y et al.·Am J Ophthalmol
2024
Five novel dysfunctional variants in the TSPAN12 gene in familial exudative vitreoretinopathy.
Wang Y et al.·Exp Eye Res
2023Functional
Pathogenic variants and associated phenotypic spectrum of TSPAN12 based on data from a large cohort.
Sun W et al.·Graefes Arch Clin Exp Ophthalmol
2021Cohort
A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR.
Peng L et al.·Mol Genet Genomic Med
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools