TMX3

Chr 18

thioredoxin related transmembrane protein 3

Also known as: PDIA13, TXNDC10

NCBI Gene: 54495ENSG00000166479UniProt: Q96JJ7

TMX3 encodes a disulfide isomerase that catalyzes protein folding in the endoplasmic reticulum and regulates endoplasmic reticulum-mitochondria contact sites through redox signaling. Mutations cause microphthalmia with autosomal dominant inheritance. The gene is moderately constrained against loss-of-function variants and shows highest expression in heart and skeletal muscle.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
6
Pubs (1 yr)
125
P/LP submissions
0%
P/LP missense
0.59
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TMX3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
123 unique Pathogenic / Likely Pathogenic· 59 VUS of 263 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
0.59LOEUF
pLI 0.004
Z-score 3.18
OE 0.34 (0.20–0.59)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.19Z-score
OE missense 0.78 (0.69–0.88)
173 obs / 223.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.34 (0.20–0.59)
0≤0.351.4
Missense OE0.78 (0.69–0.88)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 9 / 26.7Missense obs/exp: 173 / 223.0Syn Z: -0.01
DN
0.6746th %ile
GOF
0.6638th %ile
LOF
0.2484th %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

263 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic112
Likely Pathogenic11
VUS59
Likely Benign8
Benign41
Conflicting1
112
Pathogenic
11
Likely Pathogenic
59
VUS
8
Likely Benign
41
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
112
0
112
Likely Pathogenic
0
0
11
0
11
VUS
0
39
20
0
59
Likely Benign
0
3
5
0
8
Benign
0
1
40
0
41
Conflicting
—1
Total0431880232

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

View in ClinVar →

Protein Context — Lollipop Plot

TMX3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Effects of cofactors RIC-3, TMX3 and UNC-50, together with distinct subunit ratios on the agonist actions of imidacloprid on Drosophila melanogaster Dα1/Dβ1 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes.
Takayama K et al.·Pestic Biochem Physiol
2022
Optimal fluorescence and photosensitivity properties of dual-functional NaYb1-x F4:Tm x 3+ nanoparticles for applications in imaging guided photodynamic therapy.
Jiayin Z et al.·RSC Adv
2021Open AccessFunctional
Discovery of PPP2R3A and TMX3 pathogenic variants in a Zhuang family with coronary artery disease using whole-exome sequencing.
Li M et al.·Int J Clin Exp Pathol
2018
Correction: Thiol-disulfide Oxidoreductases TRX1 and TMX3 Decrease Neuronal Atrophy in a Lentiviral Mouse Model of Huntington's Disease.
Plos Currents.·PLoS Curr
2016Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

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