TMX2

Summary

TMX2 (thioredoxin related transmembrane protein 2, HGNC:30739) is a protein-coding gene on chromosome 11q12.1, encoding Thioredoxin-related transmembrane protein 2 (Q9Y320). Endoplasmic reticulum and mitochondria-associated protein that probably functions as a regulator of cellular redox state and thereby regulates protein post-translational modification, protein folding and mitochondrial activity. It is a selective cancer dependency (DepMap: 37.5% of cell lines).

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.

Source: NCBI Gene 51075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 71 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 19
• Cancer dependency (DepMap): dependent in 37.5% of screened cell lines
• MANE Select transcript: NM_015959

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30739
Approved symbol	TMX2
Name	thioredoxin related transmembrane protein 2
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	PDIA12
Ensembl gene	ENSG00000213593
Ensembl biotype	protein_coding
OMIM	616715
Entrez	51075

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 22 protein_coding, 9 nonsense_mediated_decay, 1 retained_intron

ENST00000278422, ENST00000378312, ENST00000524972, ENST00000525035, ENST00000528042, ENST00000528110, ENST00000529403, ENST00000530114, ENST00000533602, ENST00000713775, ENST00000713776, ENST00000713777, ENST00000713778, ENST00000713948, ENST00000713949, ENST00000713950, ENST00000884992, ENST00000884997, ENST00000884999, ENST00000885001, ENST00000885003, ENST00000885006, ENST00000885008, ENST00000917175, ENST00000917176, ENST00000917177, ENST00000917178, ENST00000917179, ENST00000917180, ENST00000917181, ENST00000917182, ENST00000917183

RefSeq mRNA: 10 — MANE Select: NM_015959 NM_001144012, NM_001347890, NM_001347891, NM_001347892, NM_001347893, NM_001347894, NM_001347895, NM_001347896, NM_001347898, NM_015959

CCDS: CCDS44601, CCDS7967

Canonical transcript exons

ENST00000278422 — 8 exons

Exon	Start	End
ENSE00000988983	57737913	57738026
ENSE00003515948	57737608	57737668
ENSE00003549087	57738974	57739039
ENSE00003611054	57739131	57739260
ENSE00004021230	57712593	57712807
ENSE00004021232	57738664	57738770
ENSE00004021236	57738354	57738430
ENSE00004021239	57740099	57740973

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.4838 / max 348.3015, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114320	72.4838	1822

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.86	gold quality
rectum	UBERON:0001052	97.59	gold quality
right adrenal gland	UBERON:0001233	97.06	gold quality
right adrenal gland cortex	UBERON:0035827	97.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.03	gold quality
right frontal lobe	UBERON:0002810	96.98	gold quality
metanephros cortex	UBERON:0010533	96.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.98	gold quality
transverse colon	UBERON:0001157	96.94	gold quality
islet of Langerhans	UBERON:0000006	96.92	gold quality
left adrenal gland	UBERON:0001234	96.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.86	gold quality
left adrenal gland cortex	UBERON:0035825	96.78	gold quality
right lobe of thyroid gland	UBERON:0001119	96.75	gold quality
adrenal tissue	UBERON:0018303	96.75	gold quality
prefrontal cortex	UBERON:0000451	96.74	gold quality
spinal cord	UBERON:0002240	96.74	gold quality
adrenal gland	UBERON:0002369	96.66	gold quality
cerebellar cortex	UBERON:0002129	96.64	gold quality
cerebellar hemisphere	UBERON:0002245	96.64	gold quality
colonic mucosa	UBERON:0000317	96.63	gold quality
caudate nucleus	UBERON:0001873	96.60	gold quality
adrenal cortex	UBERON:0001235	96.59	gold quality
left lobe of thyroid gland	UBERON:0001120	96.53	gold quality
body of stomach	UBERON:0001161	96.48	gold quality
anterior cingulate cortex	UBERON:0009835	96.47	gold quality
adult organism	UBERON:0007023	96.46	gold quality
cingulate cortex	UBERON:0003027	96.42	gold quality
left uterine tube	UBERON:0001303	96.40	gold quality
nucleus accumbens	UBERON:0001882	96.38	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting TMX2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-4665-5P	97.91	67.69	1536

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 37.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• molecular cloning and characterization of one member of the thioredoxin superfamily, designated as TMX2; the TMX2 cDNA consists of 1644 nucleotides and contains an open reading frame encoding a protein of 372 amino acids (PMID:12670024)
• TMX2 is enriched on the mitochondria-associated membrane. Targeting TMX to the MAM requires palmitoylation of two membrane-proximal cytosolic cysteines. (PMID:22045338)
• Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly. (PMID:31586943)
• Thioredoxin-related transmembrane protein 2 (TMX2) regulates the Ran protein gradient and importin-beta-dependent nuclear cargo transport. (PMID:31653923)
• TMX2 Dysfunction Causes Severe Brain Developmental Abnormalities. (PMID:31735293)
• TMX family genes and their association with prognosis, immune infiltration, and chemotherapy in human pan-cancer. (PMID:38147024)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmx2b	ENSDARG00000007786
mus_musculus	Tmx2	ENSMUSG00000050043
rattus_norvegicus	Tmx2	ENSRNOG00000005308
drosophila_melanogaster	CG11007	FBGN0034455
caenorhabditis_elegans		WBGENE00016446

Protein

Protein identifiers

Thioredoxin-related transmembrane protein 2 — Q9Y320 (reviewed: Q9Y320)

Alternative names: Cell proliferation-inducing gene 26 protein, Thioredoxin domain-containing protein 14

All UniProt accessions (12): A0AAQ5BGU1, A0AAQ5BGV9, A0AAQ5BGW3, A0AAQ5BGY8, A0AAQ5BH64, A0AAQ5BH71, A0AAQ5BH86, E9PLR1, E9PRL5, E9PSF0, G3V155, Q9Y320

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum and mitochondria-associated protein that probably functions as a regulator of cellular redox state and thereby regulates protein post-translational modification, protein folding and mitochondrial activity. Indirectly regulates neuronal proliferation, migration, and organization in the developing brain.

Subunit / interactions. Monomer. Homodimer; disulfide-linked. Occurs in both reduced and oxidized monomeric form. Oxidative conditions increase homodimerization. Interacts with CANX. Interacts with ATP2A2.

Subcellular location. Endoplasmic reticulum membrane. Mitochondrion membrane.

Tissue specificity. Widely expressed.

Disease relevance. Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) [MIM:618730] An autosomal recessive neurodevelopmental disorder characterized by developmental delay, severe to profound intellectual disability, congenital microcephaly, cortical polymicrogyria, lissencephaly, reduced central white matter volume, and drug-resistant epilepsy, lack of speech, absent ambulation and a progressive neurodegenerative course in most patients. Early death may occur in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The thioredoxin domain lacks the 2 redox-active cysteines, suggesting that it lacks thioredoxin activity. The di-lysine motif confers endoplasmic reticulum localization for type I membrane proteins.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y320-1	1	yes
Q9Y320-2	2

RefSeq proteins (10): NP_001137484, NP_001334819, NP_001334820, NP_001334821, NP_001334822, NP_001334823, NP_001334824, NP_001334825, NP_001334827, NP_057043* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013766	Thioredoxin_domain	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR037463	TMX2_thioredoxin_dom	Domain
IPR039101	TMX2	Family

Pfam: PF00085

UniProt features (42 total): sequence variant 10, strand 6, sequence conflict 5, helix 5, modified residue 3, topological domain 2, turn 2, signal peptide 1, chain 1, splice variant 1, mutagenesis site 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9KCM	ELECTRON MICROSCOPY	2.9
2DJ0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y320-F1	86.38	0.67

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 243, 288, 211

Mutagenesis-validated functional residues (1):

Position	Phenotype
170	increased homodimerization even in absence of oxidative stress.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 142 (showing top): TSENG_IRS1_TARGETS_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, LE_EGR2_TARGETS_UP, TCF11_01, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_HEAD_DEVELOPMENT, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, OSMAN_BLADDER_CANCER_DN, GOCC_ORGANELLE_MEMBRANE_CONTACT_SITE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_ORGANELLE_SUBCOMPARTMENT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_9, GOMF_DISULFIDE_OXIDOREDUCTASE_ACTIVITY, COULOUARN_TEMPORAL_TGFB1_SIGNATURE_UP, GOCC_ORGANELLE_ENVELOPE

GO Biological Process (1): brain development (GO:0007420)

GO Molecular Function (3): disulfide oxidoreductase activity (GO:0015036), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), endoplasmic reticulum membrane (GO:0005789), mitochondrial membrane (GO:0031966), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular membrane-bounded organelle	2
organelle membrane	2
central nervous system development	1
animal organ development	1
head development	1
oxidoreductase activity, acting on a sulfur group of donors	1
protein binding	1
binding	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane contact site	1
endomembrane system	1
cellular anatomical structure	1

Protein interactions and networks

STRING

780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMX2	TMX1	Q9H3N1	678
TMX2	TMX3	Q96JJ7	634
TMX2	TMX4	Q9H1E5	629
TMX2	PDIA2	Q13087	512
TMX2	ERP29	P30040	508
TMX2	CANX	P27824	482
TMX2	ERP27	Q96DN0	444
TMX2	ERP44	Q9BS26	419
TMX2	PDIA5	Q14554	417
TMX2	C9orf72	Q96LT7	414
TMX2	CLCN3	P51790	395
TMX2	TXN	P10599	390
TMX2	TXNDC12	O95881	370
TMX2	NALF2	O75949	366
TMX2	AGR3	Q8TD06	365

IntAct

534 interactions, top by confidence:

A	B	Type	Score
TTMP	TMX2	psi-mi:“MI:0915”(physical association)	0.670
PNLIPRP1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
THBD	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TVP23B	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM86B	TMX2	psi-mi:“MI:0915”(physical association)	0.560
SMIM1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM121	TMX2	psi-mi:“MI:0915”(physical association)	0.560
PRAF2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	TMX2	psi-mi:“MI:0915”(physical association)	0.560
AIG1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
BNIP1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM203	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM50B	TMX2	psi-mi:“MI:0915”(physical association)	0.560
MALL	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TSNARE1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
ITGAM	TMX2	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	TMX2	psi-mi:“MI:0915”(physical association)	0.560
RABAC1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
PTPN9	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM254	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMX2	RNF24	psi-mi:“MI:0915”(physical association)	0.560
YIF1A	TMX2	psi-mi:“MI:0915”(physical association)	0.560
SMCO4	TMX2	psi-mi:“MI:0915”(physical association)	0.560
SCD	TMX2	psi-mi:“MI:0915”(physical association)	0.560
PPGB	TMX2	psi-mi:“MI:0915”(physical association)	0.560
OTULINL	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TREX1	TMX2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (283): TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS), NDUFA7 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), TMX2 (Affinity Capture-MS)

ESM2 similar proteins: A2VDK9, A4R0J5, A9JRA0, B0FWK4, B8JLV7, D3ZEH5, E1BD52, P83362, Q0VCK9, Q15005, Q28250, Q28GR4, Q2TBU2, Q3SYY9, Q3T134, Q3ZAQ7, Q4R512, Q4R5B4, Q4R5E3, Q4V7U1, Q58DA4, Q5BJI9, Q5BJW3, Q5F3F5, Q5F409, Q5M8Y1, Q5RAY6, Q5RDV3, Q5RF53, Q5RFE0, Q5XIK2, Q5ZI05, Q5ZKG8, Q5ZLL0, Q62302, Q6AZ61, Q6NYF1, Q6UWH6, Q78T54, Q7ZUA6

Diamond homologs: A8WG88, Q18484, Q2TBU2, Q39241, Q4R5B4, Q58E26, Q5RF53, Q5XIK2, Q6DFS0, Q6IQC7, Q75GM1, Q7JW12, Q8TFM8, Q9D710, Q9Y320, O76003, Q39239, Q39362, Q42403, Q96419, Q9UW02, O51088, O84544, P22217, P22803, P52227, P46843, Q9DC23, A0A8M1N5Y4, Q9PJK3, Q8NBS9, Q9R6P9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

71 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	49
Likely benign	13
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
804371	NM_015959.4(TMX2):c.157C>T (p.Arg53Cys)	Pathogenic
804373	NM_015959.4(TMX2):c.166G>C (p.Gly56Arg)	Pathogenic
1030429	NM_015959.4(TMX2):c.613C>T (p.Arg205Trp)	Likely pathogenic
3024111	NM_015959.4(TMX2):c.185_188del (p.Asp62fs)	Likely pathogenic

SpliceAI

2599 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57737606:A:AG	acceptor_gain	1.0000
11:57737607:G:GG	acceptor_gain	1.0000
11:57737669:G:GG	donor_gain	1.0000
11:57737674:T:G	donor_gain	1.0000
11:57737911:A:AG	acceptor_gain	1.0000
11:57737912:G:GA	acceptor_gain	1.0000
11:57737912:G:GG	acceptor_gain	1.0000
11:57738352:A:AG	acceptor_gain	1.0000
11:57738353:G:GG	acceptor_gain	1.0000
11:57738353:GT:G	acceptor_gain	1.0000
11:57738771:G:GG	donor_gain	1.0000
11:57739272:G:GT	donor_gain	1.0000
11:57740213:GT:G	donor_gain	1.0000
11:57740233:G:GT	donor_gain	1.0000
11:57740237:GA:G	donor_gain	1.0000
11:57740242:A:AG	donor_gain	1.0000
11:57741692:G:GT	donor_gain	1.0000
11:57741731:A:T	donor_gain	1.0000
11:57741807:A:AG	acceptor_gain	1.0000
11:57741808:G:GT	acceptor_gain	1.0000
11:57741808:GC:G	acceptor_gain	1.0000
11:57741808:GCA:G	acceptor_gain	1.0000
11:57741808:GCACT:G	acceptor_gain	1.0000
11:57741951:AGCA:A	donor_gain	1.0000
11:57741952:GCA:G	donor_gain	1.0000
11:57741952:GCAG:G	donor_gain	1.0000
11:57741953:CA:C	donor_gain	1.0000
11:57741954:AG:A	donor_loss	1.0000
11:57741955:G:GG	donor_gain	1.0000
11:57741956:T:A	donor_loss	1.0000

AlphaMissense

1925 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57738761:T:C	L180P	0.999
11:57738764:C:T	S181F	0.999
11:57739000:G:A	G192E	0.999
11:57739169:C:A	P218H	0.999
11:57739213:C:T	P233S	0.999
11:57739214:C:A	P233Q	0.999
11:57740124:T:C	L257S	0.999
11:57737635:A:C	S73R	0.998
11:57737637:T:A	S73R	0.998
11:57737637:T:G	S73R	0.998
11:57737639:C:A	A74D	0.998
11:57737951:A:C	S97R	0.998
11:57737953:T:A	S97R	0.998
11:57737953:T:G	S97R	0.998
11:57737961:C:A	A100D	0.998
11:57737999:G:C	G113R	0.998
11:57738694:T:A	W158R	0.998
11:57738694:T:C	W158R	0.998
11:57738718:T:A	W166R	0.998
11:57738718:T:C	W166R	0.998
11:57738732:C:G	C170W	0.998
11:57738763:T:C	S181P	0.998
11:57738975:T:G	Y184D	0.998
11:57738996:T:C	F191L	0.998
11:57738997:T:C	F191S	0.998
11:57738998:T:A	F191L	0.998
11:57738998:T:G	F191L	0.998
11:57738999:G:T	G192W	0.998
11:57739175:T:C	L220P	0.998
11:57739213:C:A	P233T	0.998

dbSNP variants (sampled 300 via entrez): RS1000033039 (11:57722793 G>A), RS1000144659 (11:57716013 T>C), RS1000217791 (11:57716112 G>A,C,T), RS1000265715 (11:57722140 C>G), RS1000508212 (11:57715536 G>C), RS1000560997 (11:57728688 C>G,T), RS1000604635 (11:57723980 G>A,C), RS1000655769 (11:57710668 G>A), RS1000782851 (11:57726988 T>C), RS1001013893 (11:57721011 T>TG), RS1001145060 (11:57714367 T>C), RS1001146171 (11:57740619 A>G,T), RS1001160571 (11:57734179 A>C,G), RS1001202595 (11:57734223 A>G), RS1001360557 (11:57728105 T>C)

Disease associations

OMIM: gene MIM:616715 | disease phenotypes: MIM:618730

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity	Strong	Autosomal recessive
neurodevelopmental disorder	Strong	Autosomal recessive

Mondo (3): neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (MONDO:0032887), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001302	Pachygyria
HP:0001339	Lissencephaly
HP:0001347	Hyperreflexia
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002365	Hypoplasia of the brainstem
HP:0002510	Spastic tetraplegia
HP:0003593	Infantile onset
HP:0010864	Severe intellectual disability
HP:0012430	Cerebral white matter hypoplasia
HP:0025190	Bilateral tonic-clonic seizure with generalized onset

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002539_6	Schizophrenia	2.000000e-09
GCST004521_290	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST005232_71	Neuroticism	7.000000e-11
GCST006803_71	Schizophrenia	1.000000e-09
GCST010546_24	Problematic alcohol use	1.000000e-08
GCST010796_593	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_594	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_595	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_596	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_597	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_598	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_599	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_600	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_601	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_602	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_603	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_604	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST90002405_281	Reticulocyte count	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004327	electrocardiography
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs576859	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs576859	MED19, TMX2	3	1.50	1	ethanol

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation	3
Air Pollutants	increases abundance, increases expression, affects expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Cannabidiol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases abundance, increases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice