TMEFF2

Summary

TMEFF2 (transmembrane protein with EGF like and two follistatin like domains 2, HGNC:11867) is a protein-coding gene on chromosome 2q32.3, encoding Tomoregulin-2 (Q9UIK5). May be a survival factor for hippocampal and mesencephalic neurons.

This gene encodes a member of the tomoregulin family of transmembrane proteins. This protein has been shown to function as both an oncogene and a tumor suppressor depending on the cellular context and may regulate prostate cancer cell invasion. Multiple soluble forms of this protein have been identified that arise from both an alternative splice variant and ectodomain shedding. Additionally, this gene has been found to be hypermethylated in multiple cancer types. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23671 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 7 total
• MANE Select transcript: NM_016192

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11867
Approved symbol	TMEFF2
Name	transmembrane protein with EGF like and two follistatin like domains 2
Location	2q32.3
Locus type	gene with protein product
Status	Approved
Aliases	TENB2, HPP1, TR, TPEF, CT120.2
Ensembl gene	ENSG00000144339
Ensembl biotype	protein_coding
OMIM	605734
Entrez	23671

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000272771, ENST00000392314, ENST00000409056, ENST00000487771, ENST00000877059, ENST00000877060, ENST00000936874, ENST00000936875

RefSeq mRNA: 3 — MANE Select: NM_016192 NM_001305134, NM_001305145, NM_016192

CCDS: CCDS2314, CCDS82547, CCDS82548

Canonical transcript exons

ENST00000272771 — 10 exons

Exon	Start	End
ENSE00000964661	192191880	192191989
ENSE00000964662	192184354	192184483
ENSE00001128675	191956255	191956378
ENSE00001152395	191953679	191953837
ENSE00001165586	192057679	192057775
ENSE00001182093	191999060	191999208
ENSE00001182100	192179668	192179694
ENSE00001253916	191949046	191950407
ENSE00001511404	192194353	192194933
ENSE00003637794	191998262	191998321

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 98.20.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7864 / max 331.3322, expressed in 542 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32972	4.4346	494
32973	0.2764	135
32971	0.0754	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	98.20	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.05	gold quality
dorsal root ganglion	UBERON:0000044	97.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.11	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.28	gold quality
entorhinal cortex	UBERON:0002728	96.25	gold quality
corpus callosum	UBERON:0002336	96.19	gold quality
subthalamic nucleus	UBERON:0001906	95.99	gold quality
endothelial cell	CL:0000115	95.98	gold quality
inferior vagus X ganglion	UBERON:0005363	95.89	gold quality
superior vestibular nucleus	UBERON:0007227	95.83	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.61	gold quality
ventral tegmental area	UBERON:0002691	95.28	gold quality
substantia nigra pars compacta	UBERON:0001965	95.05	gold quality
globus pallidus	UBERON:0001875	94.96	gold quality
medial globus pallidus	UBERON:0002477	94.87	gold quality
parietal lobe	UBERON:0001872	94.63	gold quality
superior frontal gyrus	UBERON:0002661	94.60	gold quality
postcentral gyrus	UBERON:0002581	94.37	gold quality
medulla oblongata	UBERON:0001896	94.30	gold quality
lateral globus pallidus	UBERON:0002476	94.29	gold quality
pons	UBERON:0000988	93.97	gold quality
prefrontal cortex	UBERON:0000451	92.59	gold quality
temporal lobe	UBERON:0001871	91.95	gold quality
Ammon’s horn	UBERON:0001954	91.42	gold quality
frontal cortex	UBERON:0001870	91.35	gold quality
seminal vesicle	UBERON:0000998	91.03	gold quality
midbrain	UBERON:0001891	90.88	gold quality
cerebellar vermis	UBERON:0004720	90.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	74.30
E-HCAD-5	yes	14.67
E-ANND-3	no	4.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, FOXO3, MYC, STAT3

miRNA regulators (miRDB)

107 targeting TMEFF2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 37)

• Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. (PMID:12384516)
• Aberrant methylation of the HPP1 gene is a relative common early event in ulcerative colitis-associated colorectal carcinoma. (PMID:12460892)
• inverse correlation between TMEFF2 and c-Myc expression (PMID:12729735)
• Analysis of DNA from peripheral blood revealed that TPEF methylation was detectable in colorectal tumor patients and patients with early or pre-neoplastic lesions, but not in healthy volunteers. (PMID:15068392)
• Hypermethylation of p16, RUNX3, and HPP1 in Barreett exophagus may represent independent risk factors for the progression of Barrett esophagus to esophageal cancer. (PMID:15824739)
• A secreted form of TMEFF2 is expressed from TMEFF2 locus and may functionally interact with full-length TMEFF2, or its binding partners, and may also influence current immune-based treatment strategies (PMID:16439095)
• Hypermethylation of HPP1 is associated with primary adenocarcinomas of the small bowel (PMID:16619216)
• Methylation testing of fecal DNA using a panel of epigenetic markers (methylated SFRP2, HPP1 and MGMT) may be a simple and promising non-invasive screening method for colorectal carcinoma and precancerous lesions. (PMID:17352030)
• TMEFF2 contributes to cell proliferation in an ADAM17-dependent autocrine fashion in cells expressing this protein (PMID:17942404)
• data provides evidence to support the role of HPP1 as a tumor suppressor gene; activation of the STAT1 pathway likely represents the principal mediator of HPP1’s tumor suppressive properties (PMID:18059030)
• Methylated PAX6- or TPEF-promoters could represent biomarkers for bladder cancer. (PMID:18070176)
• Distinct TPEF/HPP1 (transmembrane protein containing epidermal growth factor) gene methylation patterns in gastric cancer indicate a field effect in gastric carcinogenesis. (PMID:18799374)
• promoter of TPEF gene is frequently hpermethylated, and associated with loss of TPEF mRNA expression in esophageal squamous cell carcinoma (PMID:19040536)
• Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma. (PMID:19288010)
• GDF15, HSPA2, TMEFF2, and VIM were identified as epigenetic biomarkers for Bladder cancer. (PMID:20975101)
• the tumor suppressor activity of TMEFF2 requires the cytoplasmic/transmembrane portion of the protein and correlates with its ability to bind to SARDH and to modulate the level of sarcosine. (PMID:21393249)
• TMEFF2 can function to regulate PDGF signaling; it is hypermethylated and downregulated in glioma and several other cancers (PMID:21559523)
• Several genes expressed at exceptionally high levels were identified associated with early oocyte development, TMEFF2, the Rho-GTPase-activating protein oligophrenin 1 (OPHN1) and the mitochondrial-encoded ATPase6 (ATP6). (PMID:22238370)
• Methylation of TMEFF2 gene is associated with colorectal neoplasia in ulcerative colitis and Crohn’s colitis. (PMID:22532293)
• Findings suggest that methylation-associated down-regulation of TMEFF2 gene may be involved in lung tumorigenesis and TMEFF2 methylation can serve as a specific blood-based biomarker for NSCLC. (PMID:22814847)
• Androgen signaling promotes eIF2alpha phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5’-UTR of TMEFF2. (PMID:23405127)
• TMEFF2 and SARDH cooperate to modulate one-carbon metabolism and invasion of prostate cancer cells. (PMID:23824605)
• c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. (PMID:24919179)
• TMEFF2 acts as a tumor suppressor in gastric cancer through direct interaction with SHP-1 and can be a potential biomarker of carcinogenesis. (PMID:24987055)
• TMEFF2 regulates the non-canonical activin/BMP4 signaling, PI3K, and Ras/ERK1/2 pathways. (PMID:25573902)
• Results suggest that TMEFF2 is a brain-enriched endogenous modulator of Abeta neurotoxicity and an enhancer of alpha-secretase processing of AbetaPP (PMID:26402097)
• TMEFF2 methylation is associated with clear cell renal cell carcinoma. (PMID:28128743)
• Differential TMEFF2 processing from a single transmembrane protein may be a general mechanism to modulate transmembrane protein levels and domains, dependent on the repertoire of ADAMs or TTSPs expressed by the target cell. (PMID:28762604)
• Our data show that candidate TSG genes QKI and TMEFF2 harbor mutational ITH as well as the frameshift mutations in GC and CRC with MSI-H. From this observation, frameshift mutations of QKI and TMEFF2 may play a role in tumorigenesis through their TSG inactivation in GC and CRC. (PMID:30614793)
• TMEFF2 expression was down-regulated in pancreatic cancer tissue compared with normal pancreas. In human pancreatic cancer cell lines, overexpression of TMEFF2 suppressed cell proliferation and enhanced apoptosis, suppressed the expression of p-STAT3, MCL1, VEGF and increased the expression of the tyrosine-specific protein phosphatase, SHP-1. (PMID:31044775)
• Study identifies a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for prostate cancer (PCa), and suggests the possibility that low TMEFF2 expression marks a distinct subclass of PCa. (PMID:31060542)
• TMEFF2 plays an important role in the initiation, development, and malignant behavior of endometrial carcinoma (EC) and can be a potential target for early diagnosis and treatment in EC (PMID:31610211)
• MiR-323-3p Targeting Transmembrane Protein with EGF-Like and 2 Follistatin Domain (TMEFF2) Inhibits Human Lung Cancer A549 Cell Apoptosis by Regulation of AKT and ERK Signaling Pathways. (PMID:32009129)
• HPP1 Ectodomain Shedding is Mediated by ADAM17 and is Necessary for Tumor Suppression in Colon Cancer. (PMID:32450419)
• Roles of a TMPO-AS1/microRNA-200c/TMEFF2 ceRNA network in the malignant behaviors and 5-FU resistance of ovarian cancer cells. (PMID:32497621)
• Long non-coding RNA LINC01963 inhibits progression of pancreatic carcinoma by targeting miR-641/TMEFF2. (PMID:32559621)
• Prognostic and clinicopathological significance of TMEFF2, SMOC-2, and SOX17 expression in endometrial carcinoma. (PMID:34339705)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmeff2a	ENSDARG00000051824
danio_rerio	tmeff2b	ENSDARG00000058699
mus_musculus	Tmeff2	ENSMUSG00000026109
rattus_norvegicus	Tmeff2	ENSRNOG00000016623

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), LAMC2 (ENSG00000058085), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF8 (ENSG00000105429), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), HSPG2 (ENSG00000142798), NTN3 (ENSG00000162068), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878), TMEFF1 (ENSG00000241697)

Protein

Protein identifiers

Tomoregulin-2 — Q9UIK5 (reviewed: Q9UIK5)

Alternative names: Hyperplastic polyposis protein 1, Transmembrane protein with EGF-like and two follistatin-like domains

All UniProt accessions (1): Q9UIK5

UniProt curated annotations — full annotation on UniProt →

Function. May be a survival factor for hippocampal and mesencephalic neurons. The shedded form up-regulates cancer cell proliferation, probably by promoting ERK1/2 phosphorylation.

Subcellular location. Membrane Membrane Secreted.

Tissue specificity. Highly expressed in adult and fetal brain, spinal cord and prostate. Expressed in all brain regions except the pituitary gland, with highest levels in amygdala and corpus callosum. Expressed in the pericryptal myofibroblasts and other stromal cells of normal colonic mucosa. Expressed in prostate carcinoma. Down-regulated in colorectal cancer. Present in Alzheimer disease plaques (at protein level). Isoform 3 is expressed weakly in testis and at high levels in normal and cancerous prostate.

Post-translational modifications. O-glycosylated; contains chondroitin sulfate glycosaminoglycans. A soluble form (TMEFF2-ECD) is produced by proteolytic shedding. This shedding can be induced by phorbol ester or pro-inflammatory cytokines such as TNFalpha, and is mediated by ADAM17.

Induction. Down-regulated in tumor cell lines in response to a high level of methylation in the 5’ region. The CpG island methylation correlates with TMEFF2 silencing in tumor cell lines.

Similarity. Belongs to the tomoregulin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UIK5-1	1	yes
Q9UIK5-2	2
Q9UIK5-3	3, TMEFF2-S

RefSeq proteins (3): NP_001292063, NP_001292074, NP_057276* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily

Pfam: PF07648

UniProt features (32 total): disulfide bond 9, splice variant 4, sequence conflict 4, domain 3, site 2, glycosylation site 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIK5-F1	68.63	0.16

Functional residue map

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

Catalytic / active sites (2): 97–98 (reactive bond); 188–189 (reactive bond)

Disulfide bonds (9): 91–121, 95–114, 103–135, 182–213, 186–206, 195–227, 265–278, 273–289, 291–300

Glycosylation sites (2): 204, 230

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, BENPORATH_ES_WITH_H3K27ME3, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_PLASMA_MEMBRANE_ORGANIZATION, MODULE_511, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_WOUND_HEALING, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_BUNDLE_ASSEMBLY, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIAL_SHEET, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION

GO Biological Process (6): cell differentiation (GO:0030154), negative regulation of cell migration (GO:0030336), wound healing, spreading of cells (GO:0044319), negative regulation of integrin biosynthetic process (GO:0045720), negative regulation of stress fiber assembly (GO:0051497), response to stress (GO:0006950)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	2
cellular anatomical structure	2
cellular developmental process	1
regulation of cell migration	1
negative regulation of cell motility	1
epiboly involved in wound healing	1
negative regulation of macromolecule biosynthetic process	1
integrin biosynthetic process	1
regulation of integrin biosynthetic process	1
negative regulation of cellular component organization	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
response to stimulus	1
binding	1

Protein interactions and networks

STRING

1092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEFF2	ERBB4	Q15303	829
TMEFF2	VIM	P08670	643
TMEFF2	TM6SF1	Q9BZW5	571
TMEFF2	SEPTIN9	Q9UHD8	570
TMEFF2	ERBB3	P21860	569
TMEFF2	EGF	P01133	563
TMEFF2	RASSF1	Q9NS23	512
TMEFF2	ALX4	Q9H161	507
TMEFF2	EPGN	Q6UW88	501
TMEFF2	TMEM37	Q8WXS4	492
TMEFF2	ERBB2	P04626	486
TMEFF2	SARDH	Q9UL12	483
TMEFF2	HS3ST2	Q9Y278	470
TMEFF2	MGMT	P16455	449
TMEFF2	BRCA1	P38398	447
TMEFF2	HLTF	Q14527	447

IntAct

35 interactions, top by confidence:

A	B	Type	Score
TMEFF2	APP	psi-mi:“MI:0914”(association)	0.590
APP	TMEFF2	psi-mi:“MI:0407”(direct interaction)	0.590
TMEFF2	APP	psi-mi:“MI:0915”(physical association)	0.590
UBIAD1	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLC	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
TMEM237	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
RIC3	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
TRHR	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
TMEFF2	UBIAD1	psi-mi:“MI:0915”(physical association)	0.560
ZDHHC15	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
TMEFF2	APP	psi-mi:“MI:0407”(direct interaction)	0.440
TMEFF2	APP	psi-mi:“MI:0915”(physical association)	0.400
TMEFF2		psi-mi:“MI:0915”(physical association)	0.370
TMEFF2	DRD2	psi-mi:“MI:0915”(physical association)	0.370
TMEFF2	HTR4	psi-mi:“MI:0915”(physical association)	0.370
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
TMEFF2	APP	psi-mi:“MI:0403”(colocalization)	0.270
TMEFF2	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.000
TMEFF2	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
TMEFF2	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
TMEFF2	TRHR	psi-mi:“MI:0915”(physical association)	0.000
ZDHHC15	TMEFF2	psi-mi:“MI:0915”(physical association)	0.000
RIC3	TMEFF2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): TMEFF2 (Affinity Capture-RNA), TMEFF2 (Two-hybrid), TMEFF2 (Two-hybrid), TMEM237 (Two-hybrid), HSF2BP (Two-hybrid), RIC3 (Two-hybrid), TRHR (Two-hybrid), NOTCH2NL (Two-hybrid), NBPF19 (Two-hybrid), TMEFF2 (Two-hybrid), TMEFF2 (Two-hybrid), BAX (Affinity Capture-Western), TMEFF2 (Affinity Capture-Western), TRIM17 (Affinity Capture-Western), TMEFF2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O35757, O62650, O75882, O95980, P07225, P09858, P10669, P17247, P19883, P21214, P21674, P26012, P26013, P27090, P30371, P31514, P31515, P47931, P49767, P50291, P61811, P61812, P97299, P97953, Q07257, Q0VBD0, Q17QD6, Q38L25, Q5RA73, Q6NW40, Q6V9H4, Q6ZQ11, Q863H1, Q86X52, Q8BFR2, Q8CI19, Q8JG54, Q8N475

Diamond homologs: A0A7H0DMZ6, O14944, O57166, P01132, P01136, P0DOP9, P0DOQ0, P0DSL4, P20494, P56974, Q00968, Q17QD6, Q5EG71, Q61521, Q6RZT5, Q776B5, Q86607, Q8V307, Q924X1, Q9J524, Q9JFH4, Q9QYM9, Q9UIK5, Q9Z0L5, A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3, O00468, O00634, O09118, O15230, O62650, O75094, O75445, O88280

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2075 predictions. Top by Δscore:

Variant	Effect	Δscore
2:191953675:TGA:T	donor_loss	1.0000
2:191953676:GACCT:G	donor_loss	1.0000
2:191953678:C:CT	donor_loss	1.0000
2:191953835:CAC:C	acceptor_gain	1.0000
2:191953837:CCTGG:C	acceptor_loss	1.0000
2:191953838:CTGG:C	acceptor_loss	1.0000
2:191956375:TTCT:T	acceptor_gain	1.0000
2:191956377:CT:C	acceptor_gain	1.0000
2:191998324:G:C	acceptor_gain	1.0000
2:191998327:T:TC	acceptor_gain	1.0000
2:191999055:ATTAC:A	donor_loss	1.0000
2:191999056:TTA:T	donor_loss	1.0000
2:191999057:TAC:T	donor_loss	1.0000
2:191999058:ACCTT:A	donor_loss	1.0000
2:191999059:C:G	donor_loss	1.0000
2:191999204:CACAC:C	acceptor_gain	1.0000
2:191999205:ACAC:A	acceptor_gain	1.0000
2:191999205:ACACC:A	acceptor_loss	1.0000
2:191999206:CAC:C	acceptor_gain	1.0000
2:191999206:CACC:C	acceptor_gain	1.0000
2:191999207:AC:A	acceptor_gain	1.0000
2:191999207:ACCTA:A	acceptor_loss	1.0000
2:191999208:CC:C	acceptor_gain	1.0000
2:191999208:CCTAA:C	acceptor_loss	1.0000
2:191999209:C:CC	acceptor_gain	1.0000
2:191999209:C:T	acceptor_gain	1.0000
2:191999209:CTA:C	acceptor_loss	1.0000
2:191999210:T:A	acceptor_loss	1.0000
2:192057673:TATTA:T	donor_loss	1.0000
2:192057675:TTA:T	donor_loss	1.0000

AlphaMissense

2475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:191953808:C:G	C300S	1.000
2:191953809:A:T	C300S	1.000
2:191999106:A:C	C213W	1.000
2:191999107:C:A	C213F	1.000
2:191999107:C:G	C213S	1.000
2:191999107:C:T	C213Y	1.000
2:191999108:A:G	C213R	1.000
2:191999108:A:T	C213S	1.000
2:191999111:A:G	S212P	1.000
2:191999128:C:G	C206S	1.000
2:191999128:C:T	C206Y	1.000
2:191999129:A:G	C206R	1.000
2:191999129:A:T	C206S	1.000
2:191999161:C:G	C195S	1.000
2:191999162:A:T	C195S	1.000
2:191999187:A:C	C186W	1.000
2:191999188:C:G	C186S	1.000
2:191999188:C:T	C186Y	1.000
2:191999189:A:G	C186R	1.000
2:191999189:A:T	C186S	1.000
2:191999200:C:A	C182F	1.000
2:191999200:C:G	C182S	1.000
2:191999200:C:T	C182Y	1.000
2:191999201:A:G	C182R	1.000
2:191999201:A:T	C182S	1.000
2:191999205:A:C	C180W	1.000
2:191999206:C:G	C180S	1.000
2:191999206:C:T	C180Y	1.000
2:191999207:A:G	C180R	1.000
2:191999207:A:T	C180S	1.000

dbSNP variants (sampled 300 via entrez): RS1000020137 (2:191977324 G>A,T), RS1000020483 (2:192072967 T>A), RS1000039580 (2:192025943 G>A), RS1000052702 (2:192157147 A>G), RS1000061060 (2:192135806 C>T), RS1000064084 (2:192142651 T>C), RS1000071896 (2:192155540 G>A), RS1000095252 (2:192052910 A>G), RS1000107546 (2:192114160 A>G), RS1000109391 (2:192024225 C>A), RS1000130040 (2:191970126 A>C,T), RS1000143478 (2:191961171 G>A,T), RS1000144257 (2:192181783 G>A,C), RS1000148690 (2:192064938 G>A,C), RS1000165228 (2:191950523 G>A,T)

Disease associations

OMIM: gene MIM:605734 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000108_1	Diabetes (incident)	7.000000e-07
GCST001099_16	Sudden cardiac arrest	4.000000e-06
GCST005331_1	CSF tryptophan concentration in tuberculous meningitis	3.000000e-06
GCST007324_145	Adventurousness	2.000000e-09
GCST009028_13	Adverse response to drug	5.000000e-08
GCST010988_196	Adult body size	1.000000e-08
GCST011768_13	Schizophrenia	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004278	sudden cardiac arrest
EFO:0008534	tryptophan measurement
EFO:0008579	risk-taking behaviour
EFO:0009658	adverse effect

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3738883	TMEFF2		0.00	0

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	8
bisphenol A	decreases expression, decreases methylation	2
mono-(2-ethylhexyl)phthalate	decreases expression	2
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	2
entinostat	affects cotreatment, decreases expression, increases expression	2
Vorinostat	affects cotreatment, increases expression, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Dihydrotestosterone	increases expression, decreases reaction, affects reaction	2
Tretinoin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
methylmercuric chloride	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression, decreases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
rutecarpine	decreases expression	1
bicalutamide	increases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Clotrimazole	increases phosphorylation, increases expression	1
Dactinomycin	decreases reaction, increases expression	1

Clinical trials (associated diseases)

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