TMX2

Chr 11AR

thioredoxin related transmembrane protein 2

Also known as: CGI-31, NEDMCMS, PDIA12, PIG26, TXNDC14

NCBI Gene: 51075ENSG00000213593UniProt: Q9Y320

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This protein is enriched on the mitochondria-associated-membrane of the ER via palmitoylation of two of its cytosolically exposed cysteines. [provided by RefSeq, Jan 2017]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticityMIM #618730
AR
88
ClinVar variants
19
Pathogenic / LP
0.65
pLI score
0
Active trials
Clinical Summary— TMX2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 53 VUS of 88 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.
0.47LOEUF
pLI 0.647
Z-score 3.07
OE 0.18 (0.08–0.47)
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.
0.22Z-score
OE missense 0.95 (0.84–1.08)
164 obs / 172.1 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 (0.08–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.84–1.08)
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.1.30
0≤1.21.6
LoF obs/exp: 3 / 16.4Missense obs/exp: 164 / 172.1Syn Z: -1.87

ClinVar Variant Classifications

88 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic6
VUS53
Likely Benign12
Benign1
Conflicting3
13
Pathogenic
6
Likely Pathogenic
53
VUS
12
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
3
8
0
13
Likely Pathogenic
1
1
4
0
6
VUS
2
45
6
0
53
Likely Benign
0
3
2
7
12
Benign
0
0
0
1
1
Conflicting
—3
Total55220888

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

View in ClinVar →

Protein Context — Lollipop Plot

TMX2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMX2-related primary microcephaly, cortical malformation, and epileptic encephalopathy

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity

MIM #618730

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Multi-omic underpinnings of epigenetic aging and human longevity.
Mavromatis LA et al.·Nat Commun
2023
TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.
Vandervore LV et al.·Am J Hum Genet
2019
Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly.
Ghosh SG et al.·J Med Genet
2020
Use of an aggressive MCF-7 cell line variant, TMX2-28, to study cell invasion in breast cancer.
Gozgit JM et al.·Mol Cancer Res
2006
Phenotypic changes in MCF-7 cells during prolonged exposure to tamoxifen.
Fasco MJ et al.·Mol Cell Endocrinol
2003
Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing.
Tan W et al.·Braz J Psychiatry
2024Cohort
Genome-wide association studies and fine-mapping identify genomic loci for n-3 and n-6 polyunsaturated fatty acids in Hispanic American and African American cohorts.
Yang C et al.·Commun Biol
2023Cohort
PLD1 is overexpressed in an ER-negative MCF-7 cell line variant and a subset of phospho-Akt-negative breast carcinomas.
Gozgit JM et al.·Br J Cancer
2007
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