TMTC3

Summary

TMTC3 (transmembrane O-mannosyltransferase targeting cadherins 3, HGNC:26899) is a protein-coding gene on chromosome 12q21.32, encoding Protein O-mannosyl-transferase TMTC3 (Q6ZXV5). Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

This gene encodes a protein that belongs to the transmembrane and tetratricopeptide repeat-containing protein family.

Source: NCBI Gene 160418 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lissencephaly 8 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 294 total — 9 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 54
• Druggable target: yes
• MANE Select transcript: NM_181783

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26899
Approved symbol	TMTC3
Name	transmembrane O-mannosyltransferase targeting cadherins 3
Location	12q21.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ90492, SMILE
Ensembl gene	ENSG00000139324
Ensembl biotype	protein_coding
OMIM	617218
Entrez	160418

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 nonsense_mediated_decay

ENST00000266712, ENST00000547034, ENST00000549011, ENST00000551088, ENST00000869786, ENST00000920415, ENST00000920416, ENST00000920417

RefSeq mRNA: 5 — MANE Select: NM_181783 NM_001366574, NM_001366579, NM_001366580, NM_001366583, NM_181783

CCDS: CCDS9032

Canonical transcript exons

ENST00000266712 — 14 exons

Exon	Start	End
ENSE00000937577	88192604	88192830
ENSE00001096853	88190453	88190622
ENSE00001096858	88188843	88188946
ENSE00001134701	88172597	88172745
ENSE00001134711	88166330	88166582
ENSE00001134726	88160114	88160229
ENSE00001134735	88154288	88154387
ENSE00001134744	88153291	88153509
ENSE00001234125	88160679	88160851
ENSE00001313649	88148288	88148504
ENSE00001432039	88194838	88199887
ENSE00002360111	88142307	88142487
ENSE00003521866	88174607	88174727
ENSE00003605314	88176208	88176319

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 97.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1162 / max 172.2434, expressed in 1780 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127204	9.4451	1710
127205	7.6711	1653

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.23	gold quality
gingival epithelium	UBERON:0001949	93.15	gold quality
upper leg skin	UBERON:0004262	92.50	gold quality
gingiva	UBERON:0001828	92.38	gold quality
upper arm skin	UBERON:0004263	92.16	gold quality
epithelial cell of pancreas	CL:0000083	91.53	gold quality
skin of hip	UBERON:0001554	91.50	gold quality
calcaneal tendon	UBERON:0003701	91.04	gold quality
esophagus squamous epithelium	UBERON:0006920	90.81	gold quality
visceral pleura	UBERON:0002401	89.62	gold quality
kidney epithelium	UBERON:0004819	88.90	gold quality
adrenal tissue	UBERON:0018303	88.21	gold quality
bronchial epithelial cell	CL:0002328	88.14	gold quality
epithelium of nasopharynx	UBERON:0001951	88.03	gold quality
middle temporal gyrus	UBERON:0002771	88.01	gold quality
bronchus	UBERON:0002185	87.56	gold quality
ileal mucosa	UBERON:0000331	87.54	gold quality
parietal pleura	UBERON:0002400	87.39	gold quality
nasal cavity epithelium	UBERON:0005384	87.27	gold quality
penis	UBERON:0000989	87.12	gold quality
mammalian vulva	UBERON:0000997	87.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.02	gold quality
oral cavity	UBERON:0000167	86.93	gold quality
palpebral conjunctiva	UBERON:0001812	86.87	gold quality
tendon	UBERON:0000043	86.57	gold quality
seminal vesicle	UBERON:0000998	86.46	gold quality
entorhinal cortex	UBERON:0002728	86.26	gold quality
endometrium	UBERON:0001295	85.35	gold quality
jejunal mucosa	UBERON:0000399	85.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

228 targeting TMTC3, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4482-3P	99.98	72.50	3147

Literature-anchored findings (GeneRIF, showing 6)

• that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation. (PMID:21603654)
• SMILE is a novel transgene specifying both bronchial smooth muscle and lung alveolar myofibroblast lineages, contributing to the understanding of the biological control of the development of these cells. (PMID:21956870)
• O-mannosylation pathway dedicated to cadherins/ protocadherins orchestrated by the four TMTC1-4 genes (PMID:28973932)
• Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites. (PMID:33436046)
• The deep infiltrating endometriosis tissue has lower T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor than endometrioma tissue. (PMID:34794738)
• A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway. (PMID:35982901)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmtc3	ENSDARG00000062846
mus_musculus	Tmtc3	ENSMUSG00000036676
rattus_norvegicus	Tmtc3	ENSRNOG00000006749
drosophila_melanogaster	Tmtc3	FBGN0020312

Paralogs (14): IFT88 (ENSG00000032742), TTC7A (ENSG00000068724), TMTC4 (ENSG00000125247), TMTC1 (ENSG00000133687), TTC6 (ENSG00000139865), BBS4 (ENSG00000140463), TTC13 (ENSG00000143643), OGT (ENSG00000147162), CFAP70 (ENSG00000156042), TTC8 (ENSG00000165533), TTC7B (ENSG00000165914), TTC16 (ENSG00000167094), TMTC2 (ENSG00000179104), TTC34 (ENSG00000215912)

Protein

Protein identifiers

Protein O-mannosyl-transferase TMTC3 — Q6ZXV5 (reviewed: Q6ZXV5)

Alternative names: Protein SMILE, Transmembrane O-mannosyltransferase targeting cadherins 3, Transmembrane and tetratricopeptide repeat-containing 3

All UniProt accessions (4): Q6ZXV5, F8VR71, F8VRY4, F8W044

UniProt curated annotations — full annotation on UniProt →

Function. Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3. Involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response.

Subcellular location. Membrane. Endoplasmic reticulum.

Disease relevance. Lissencephaly 8 (LIS8) [MIM:617255] A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex. LIS8 patients manifest delayed psychomotor development, intellectual disability with poor or absent speech, early-onset refractory seizures, hypotonia, cortical gyral abnormalities, and hypoplasia of the corpus callosum, brainstem and cerebellum. LIS8 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the TMTC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZXV5-1	1	yes
Q6ZXV5-2	2

RefSeq proteins (5): NP_001353503, NP_001353508, NP_001353509, NP_001353512, NP_861448* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013618	TMTC_DUF1736	Domain
IPR019734	TPR_rpt	Repeat

Pfam: PF08409, PF13174, PF13181, PF13431

Catalyzed reactions (Rhea), 2 shown:

• a di-trans,poly-cis-dolichyl beta-D-mannosyl phosphate + L-seryl-[protein] = 3-O-(alpha-D-mannosyl)-L-seryl-[protein] + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:17377)
• a di-trans,poly-cis-dolichyl beta-D-mannosyl phosphate + L-threonyl-[protein] = 3-O-(alpha-D-mannosyl)-L-threonyl-[protein] + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:53396)

UniProt features (51 total): topological domain 11, transmembrane region 11, repeat 9, sequence conflict 9, glycosylation site 3, compositionally biased region 2, sequence variant 2, chain 1, region of interest 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZXV5-F1	87.83	0.76

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 (1): 503

Glycosylation sites (3): 494, 541, 865

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 259 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, chr12q21, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEOLYSIS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEOLYSIS

GO Biological Process (5): response to endoplasmic reticulum stress (GO:0034976), protein O-linked glycosylation via mannose (GO:0035269), positive regulation of proteasomal protein catabolic process (GO:1901800), obsolete protein glycosylation (GO:0006486), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (4): mannosyltransferase activity (GO:0000030), dolichyl-phosphate-mannose-protein mannosyltransferase activity (GO:0004169), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to stress	1
protein O-linked glycosylation	1
proteasomal protein catabolic process	1
positive regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of metabolic process	1
macromolecule metabolic process	1
hexosyltransferase activity	1
mannosyltransferase activity	1
protein O-linked glycosylation via mannose	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMTC3	XPO6	Q96QU8	614
TMTC3	ERMARD	Q5T6L9	524
TMTC3	POMT1	Q9Y6A1	490
TMTC3	PIGB	Q92521	457
TMTC3	DPY19L4	Q7Z388	455
TMTC3	POMT2	Q9UKY4	454
TMTC3	QSER1	Q2KHR3	426
TMTC3	RNF5	Q99942	412
TMTC3	TMEM209	Q96SK2	410
TMTC3	TMEM179B	Q7Z7N9	394
TMTC3	SCAF8	Q9UPN6	379
TMTC3	PIGZ	Q86VD9	376
TMTC3	ARFGEF2	Q9Y6D5	376
TMTC3	TMEM201	Q5SNT2	375
TMTC3	POC1B	Q8TC44	371

IntAct

73 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
DAB1	TMTC3	psi-mi:“MI:0915”(physical association)	0.560
TMTC3	DAB1	psi-mi:“MI:0915”(physical association)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
NCEH1	CLGN	psi-mi:“MI:0914”(association)	0.530
ANKRD12	TMTC3	psi-mi:“MI:0915”(physical association)	0.400
TMTC3	MAF1b1	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
DNAJB1	HSPA8	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CDH5	NBAS	psi-mi:“MI:0914”(association)	0.350
ZACN	FAM234B	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRC4	RAP1BL	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
KIR2DS3	RTL8C	psi-mi:“MI:0914”(association)	0.350
CHRNB4	GPR89A	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350

BioGRID (141): TMTC3 (Two-hybrid), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), COTL1 (Co-fractionation), TMTC3 (Proximity Label-MS), TMTC3 (Proximity Label-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS)

ESM2 similar proteins: A6X919, A8Y3M2, D4AD75, E2RG47, F1PJP5, F1Q8R9, F1QF89, O13898, O42933, O94335, P31382, P33775, P34413, P42934, P46971, P46977, P47190, P52867, P53868, P54002, Q23361, Q290J8, Q29IL2, Q2KJI2, Q2U0S9, Q3TDQ1, Q3UVK0, Q59X23, Q5A688, Q5ACU3, Q5ADM9, Q5RCE2, Q6F2Z1, Q6NUT2, Q6ZXV5, Q7Z2K6, Q8BGQ4, Q8BRH0, Q8N394, Q8TCJ2

Diamond homologs: A8BFN4, O13797, Q6ZXV5, Q8BRH0, Q8LP10, Q20144, Q3UV71, Q56A06, Q5T4D3, Q6DCD5, Q7K4B6, Q8BG19, Q8IUR5, Q8N394, Q9VF81, Q9VQE9, Q9V3X5, A0A1L8FDW4, C4R2L0, O09012, O70525, O74711, O94325, P17883, P33292, P35056, P50542, Q01495, Q04364, Q1RMV0, Q2M2R8, Q5ZMQ9, Q6BM14, Q6CT48, Q6FM42, Q752X0, Q8C437, Q8IYB4, Q920N5, Q925N3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neurotransmitter receptors and postsynaptic signal transmission	7	9.6×	7e-04
Transmission across Chemical Synapses	7	7.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
acetylcholine receptor signaling pathway	6	41.1×	5e-06
membrane depolarization	5	28.1×	2e-04
monoatomic ion transmembrane transport	8	18.3×	5e-06
ERAD pathway	7	13.9×	2e-04
protein folding	8	9.1×	4e-04
negative regulation of cell population proliferation	12	5.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	155
Likely benign	83
Benign	20

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1456984	NM_181783.4(TMTC3):c.1966C>T (p.Arg656Ter)	Pathogenic
2002666	NM_181783.4(TMTC3):c.872_875dup (p.Trp292fs)	Pathogenic
2126105	NM_181783.4(TMTC3):c.1221G>A (p.Trp407Ter)	Pathogenic
372273	NM_181783.4(TMTC3):c.1462del (p.Arg488fs)	Pathogenic
372274	NM_181783.4(TMTC3):c.2617C>T (p.Gln873Ter)	Pathogenic
372275	NM_181783.4(TMTC3):c.1959_1960insTT (p.Arg654fs)	Pathogenic
372277	NM_181783.4(TMTC3):c.3G>A (p.Met1Ile)	Pathogenic
4710001	NM_181783.4(TMTC3):c.212G>A (p.Arg71His)	Pathogenic
4804940	NM_181783.4(TMTC3):c.785del (p.Pro262fs)	Pathogenic
2690766	NM_181783.4(TMTC3):c.795dup (p.Arg266fs)	Likely pathogenic
2882124	NM_181783.4(TMTC3):c.950A>G (p.Asp317Gly)	Likely pathogenic
3064748	NM_181783.4(TMTC3):c.838C>T (p.Gln280Ter)	Likely pathogenic
372276	NM_181783.4(TMTC3):c.199C>G (p.His67Asp)	Likely pathogenic
3780722	NM_181783.4(TMTC3):c.1432+1G>A	Likely pathogenic
4776947	NM_181783.4(TMTC3):c.2616_2619del (p.Lys872fs)	Likely pathogenic
4846952	NM_181783.4(TMTC3):c.1230_1233del (p.Ser411fs)	Likely pathogenic
4848517	NM_181783.4(TMTC3):c.2338_2341del (p.Val780fs)	Likely pathogenic

SpliceAI

2133 predictions. Top by Δscore:

Variant	Effect	Δscore
12:88153507:GCA:G	donor_gain	1.0000
12:88153510:G:GG	donor_gain	1.0000
12:88154384:A:AG	donor_gain	1.0000
12:88154388:G:GG	donor_gain	1.0000
12:88156943:GA:G	donor_gain	1.0000
12:88156945:G:GG	donor_gain	1.0000
12:88160106:A:G	acceptor_gain	1.0000
12:88160112:A:AG	acceptor_gain	1.0000
12:88160113:G:GA	acceptor_gain	1.0000
12:88160226:GGGG:G	donor_gain	1.0000
12:88160227:GGGG:G	donor_gain	1.0000
12:88160677:A:AG	acceptor_gain	1.0000
12:88160678:G:GG	acceptor_gain	1.0000
12:88173090:G:GG	donor_gain	1.0000
12:88176202:TTTAA:T	acceptor_loss	1.0000
12:88176203:TTAA:T	acceptor_loss	1.0000
12:88176204:TAA:T	acceptor_loss	1.0000
12:88176206:A:G	acceptor_gain	1.0000
12:88176207:GGTA:G	acceptor_gain	1.0000
12:88176207:GGTAA:G	acceptor_gain	1.0000
12:88176315:GCCAG:G	donor_gain	1.0000
12:88176320:GT:G	donor_loss	1.0000
12:88176321:T:G	donor_loss	1.0000
12:88188944:CAAGT:C	donor_loss	1.0000
12:88188946:AG:A	donor_loss	1.0000
12:88188947:G:GG	donor_gain	1.0000
12:88188947:GTAAG:G	donor_loss	1.0000
12:88188948:TAAG:T	donor_loss	1.0000
12:88188949:A:AG	donor_loss	1.0000
12:88190447:A:AG	acceptor_gain	1.0000

AlphaMissense

6020 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000068136 (12:88155403 A>G), RS1000273688 (12:88187102 A>G), RS1000326180 (12:88152968 A>C), RS1000368066 (12:88169733 G>A), RS1000419114 (12:88170020 G>A), RS1000436012 (12:88145711 C>T), RS1000457986 (12:88197871 A>G), RS1000510133 (12:88198278 C>A,T), RS1000528552 (12:88159972 T>A), RS1000630604 (12:88152654 T>G), RS1000707736 (12:88167575 T>C), RS1000772361 (12:88183748 C>G), RS1000870212 (12:88163926 G>C), RS1000914530 (12:88149612 A>G), RS1000915904 (12:88174885 G>A)

Disease associations

OMIM: gene MIM:617218 | disease phenotypes: MIM:617255

GenCC curated gene-disease

Disease	Classification	Inheritance
lissencephaly 8	Strong	Autosomal recessive
periventricular nodular heterotopia	Supportive	Autosomal dominant

Mondo (2): lissencephaly 8 (MONDO:0014992), periventricular nodular heterotopia (MONDO:0020341)

Orphanet (0):

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000648	Optic atrophy
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000963	Thin skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001321	Cerebellar hypoplasia
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001643	Patent ductus arteriosus
HP:0001654	Abnormal heart valve morphology
HP:0001659	Aortic regurgitation
HP:0001762	Talipes equinovarus
HP:0001892	Abnormal bleeding
HP:0002020	Gastroesophageal reflux
HP:0002021	Pyloric stenosis
HP:0002079	Hypoplasia of the corpus callosum
HP:0002085	Occipital encephalocele
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002194	Delayed gross motor development
HP:0002282	Gray matter heterotopia
HP:0002365	Hypoplasia of the brainstem
HP:0002500	Abnormal cerebral white matter morphology

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002595_19	Clozapine-induced agranulocytosis	6.000000e-06
GCST006988_145	Blond vs. brown/black hair color	8.000000e-12
GCST006988_156	Blond vs. brown/black hair color	2.000000e-10
GCST006988_9	Blond vs. brown/black hair color	6.000000e-85
GCST006989_6	Brown vs. black hair color	3.000000e-30

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D054091	Periventricular Nodular Heterotopia	C10.500.507.450.750; C16.131.666.507.450.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465323 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
bisphenol A	increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Carbamazepine	affects expression	1
Coal	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylstilbestrol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5338474	Binding	Binding affinity to Tmtc3 (unknown origin) assessed as fold change in protein upregulation at 200 uM preincubated for 2 hrs followed by pronase addition and measured after 30 mins by coomassie blue staining based SDS-PAGE gel analysis	Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans. — J Nat Prod

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2MC	HAP1 TMTC3 (-) 1	Cancer cell line	Male
CVCL_E2MD	HAP1 TMTC3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.