TMCO1

Summary

TMCO1 (transmembrane and coiled-coil domains 1, HGNC:18188) is a protein-coding gene on chromosome 1q24.1, encoding Calcium load-activated calcium channel (Q9UM00). Endoplasmic reticulum (ER) calcium-selective channel preventing intracellular Ca2(+) stores from overfilling and maintaining calcium homeostasis in the ER.

This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 54499 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebrofaciothoracic dysplasia (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 31
• Clinical variants (ClinVar): 103 total — 8 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 93
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_019026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18188
Approved symbol	TMCO1
Name	transmembrane and coiled-coil domains 1
Location	1q24.1
Locus type	gene with protein product
Status	Approved
Aliases	HP10122
Ensembl gene	ENSG00000143183
Ensembl biotype	protein_coding
OMIM	614123
Entrez	54499

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 nonsense_mediated_decay

ENST00000367881, ENST00000464650, ENST00000465705, ENST00000476143, ENST00000481278, ENST00000580248, ENST00000612311, ENST00000628579, ENST00000868461, ENST00000868462, ENST00000868463

RefSeq mRNA: 3 — MANE Select: NM_019026 NM_001256164, NM_001256165, NM_019026

CCDS: CCDS1251

Canonical transcript exons

ENST00000367881 — 7 exons

Exon	Start	End
ENSE00001445848	165726795	165728121
ENSE00001882266	165768682	165768868
ENSE00001914290	165743167	165743311
ENSE00003511910	165759525	165759584
ENSE00003527458	165752102	165752169
ENSE00003551428	165768192	165768269
ENSE00003658976	165754228	165754274

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 99.3821 / max 1130.1496, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15740	94.1363	1824
15738	2.9705	1370
15739	2.2753	1239

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.00	gold quality
choroid plexus epithelium	UBERON:0003911	98.41	gold quality
rectum	UBERON:0001052	98.35	gold quality
islet of Langerhans	UBERON:0000006	98.32	gold quality
jejunal mucosa	UBERON:0000399	97.91	gold quality
gall bladder	UBERON:0002110	97.71	gold quality
colonic mucosa	UBERON:0000317	97.67	gold quality
mucosa of transverse colon	UBERON:0004991	97.64	gold quality
bronchial epithelial cell	CL:0002328	97.57	gold quality
tendon	UBERON:0000043	97.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.51	gold quality
stromal cell of endometrium	CL:0002255	97.50	gold quality
duodenum	UBERON:0002114	97.39	gold quality
adrenal tissue	UBERON:0018303	97.37	gold quality
palpebral conjunctiva	UBERON:0001812	97.29	gold quality
seminal vesicle	UBERON:0000998	97.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.03	gold quality
adult organism	UBERON:0007023	96.92	gold quality
right adrenal gland cortex	UBERON:0035827	96.86	gold quality
nephron tubule	UBERON:0001231	96.85	gold quality
ileal mucosa	UBERON:0000331	96.82	gold quality
right adrenal gland	UBERON:0001233	96.82	gold quality
left adrenal gland	UBERON:0001234	96.81	gold quality
ventricular zone	UBERON:0003053	96.68	gold quality
pigmented layer of retina	UBERON:0001782	96.63	gold quality
left adrenal gland cortex	UBERON:0035825	96.56	gold quality
adrenal gland	UBERON:0002369	96.42	gold quality
tendon of biceps brachii	UBERON:0008188	96.38	gold quality
germinal epithelium of ovary	UBERON:0001304	96.37	gold quality
epithelium of bronchus	UBERON:0002031	96.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	32.63
E-MTAB-6524	no	139.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

145 targeting TMCO1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• This report shows a TMCO1 sequence variant being associated with a genetic disorder in humans. (PMID:20018682)
• We report a genome-wide association study for open-angle glaucoma (OAG) blindness at tnco1 and cdkn2b loci. (PMID:21532571)
• Intraocular pressure (IOP)was significantly associated with rs11656696, located in GAS7 at 17p13.1 and with rs7555523, located in TMCO1 at 1q24.1.These data suggest that we have identified two clinically relevant genes involved in IOP regulation. (PMID:22570627)
• This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene. (PMID:22714896)
• We identified two nominally significant SNPs (P < 0.05), including rs7518099 and rs2814471 in TMCO1, in primary open angle glaucoma. (PMID:23963167)
• TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia. (PMID:24194475)
• The significant association of three common variants in TMCO1, ATOH7, and CAV1 with primary open angle, primary angle closure, and pseudoexfoliation glaucoma was found in Pakistani cohorts. (PMID:25489222)
• TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort. (PMID:27707548)
• TMCO1 recruited the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell-cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, whereas T33A and S60A mutants recovered, tumor size in xenograft mice. (PMID:28972042)
• Thus we provide evidence that cerebrofaciothoracic dysplasia (CFTD) may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1. (PMID:30556256)
• Our results demonstrate that a SNP downstream of TMCO1, rs4657473, is associated with POAG in an AA population. Our studies suggest a regulatory role for the previously POAG-associated locus near the TMCO1 gene that may affect gene expression. (PMID:30862618)
• CDKN2B-AS1 can inhibit the transcription of ADAM10 via DNMT1-mediated ADAM10 DNA methylation, consequently preventing inflammatory response of atherosclerosis and promoting cholesterol efflux. (PMID:30926762)
• An essential role of TMCO1 in osteogenesis mediated by local Ca(2+)/CaMKII signaling in osteoblasts.TMCO1 levels were significantly decreased in bone from both osteoporosis patients. (PMID:30962442)
• A novel biallelic loss-of-function mutation in TMCO1 gene confirming and expanding the phenotype spectrum of cerebro-facio-thoracic dysplasia. (PMID:31102500)
• iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca(2+) homeostasis and control tumor growth and drug resistance. (PMID:35121659)
• Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature. (PMID:36708876)
• Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer. (PMID:37527660)
• TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance. (PMID:38372107)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmco1	ENSDARG00000069099
mus_musculus	Tmco1	ENSMUSG00000052428
rattus_norvegicus	Tmco1	ENSRNOG00000003928
drosophila_melanogaster	CG10470	FBGN0032746
caenorhabditis_elegans		WBGENE00009045

Protein

Protein identifiers

Calcium load-activated calcium channel — Q9UM00 (reviewed: Q9UM00)

Alternative names: GEL complex subunit TMCO1, Transmembrane and coiled-coil domain-containing protein 1, Transmembrane and coiled-coil domains protein 4, Xenogeneic cross-immune protein PCIA3

All UniProt accessions (7): Q9UM00, A0A0D9SEL8, B7Z591, J3KS45, J3KTQ7, J3QQY2, J3QRB3

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER) calcium-selective channel preventing intracellular Ca2(+) stores from overfilling and maintaining calcium homeostasis in the ER. In response to endoplasmic reticulum (ER) Ca2(+) overloading, assembles into a homotetramer, forming a functional calcium-selective channel facilitating Ca2(+) release. Mediates ER Ca2(+) homeostasis in osteoblasts and plays a key role in bone formation, via the CaMKII-HDAC4-RUNX2 signaling axis. Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane.

Subunit / interactions. Homodimer and homotetramer. Homodimer under resting conditions; forms homotetramers following ER calcium overload. Component of the GET- and EMC-like (GEL) complex, composed of RAB5IF/OPTI and TMCO1. The GEL complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47). The MPT complex associates with the SEC61 complex.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Mitochondrion membrane.

Tissue specificity. Widely expressed in adult and fetal tissues, with higher levels in thymus, prostate, testis and small intestine and lower levels in brain, placenta, lung and kidney. Present in most tissues in the eye, including the trabecular meshwork and retina (at protein level).

Disease relevance. Craniofacial dysmorphism, skeletal anomalies and impaired intellectual development syndrome 1 (CFSMR1) [MIM:213980] An autosomal recessive disorder characterized by craniofacial and skeletal anomalies, associated with intellectual disability. Typical craniofacial dysmorphism include brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represent skeletal anomalies. The disease is caused by variants affecting the gene represented in this entry. Glaucoma, primary open angle (POAG) [MIM:137760] A complex and genetically heterogeneous ocular disorder characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. In some cases, POAG shows digenic inheritance involving mutations in CYP1B1 and MYOC genes. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the TMCO1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UM00-3	1	yes
Q9UM00-2	2
Q9UM00-1	3

RefSeq proteins (3): NP_001243093, NP_001243094, NP_061899* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002809	EMC3/TMCO1	Family
IPR008559	TMCO1	Family

Pfam: PF01956

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (20 total): topological domain 5, transmembrane region 3, modified residue 2, splice variant 2, sequence variant 2, mutagenesis site 2, chain 1, coiled-coil region 1, sequence conflict 1, intramembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6W6L	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM00-F1	64.41	0.00

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 (2): 111, 239

Mutagenesis-validated functional residues (2):

Position	Phenotype
191	abolishes the calcium channel activity.
191	retains some of the calcium channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 453 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MONOATOMIC_CATION_TRANSPORT, PATIL_LIVER_CANCER, ONKEN_UVEAL_MELANOMA_UP, GOBP_ER_NUCLEUS_SIGNALING_PATHWAY, GGAANCGGAANY_UNKNOWN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_CALCIUM_ION_HOMEOSTASIS, GOBP_OSSIFICATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MONOATOMIC_ION_HOMEOSTASIS

GO Biological Process (8): ossification (GO:0001503), ER overload response (GO:0006983), endoplasmic reticulum calcium ion homeostasis (GO:0032469), calcium ion transmembrane transport (GO:0070588), multi-pass transmembrane protein insertion into ER membrane (GO:0160063), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (3): calcium channel activity (GO:0005262), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (9): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), mitochondrial membrane (GO:0031966), multi-pass translocon complex (GO:0160064), mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
intracellular membrane-bounded organelle	3
cellular anatomical structure	2
endomembrane system	2
organelle membrane	2
multicellular organismal process	1
ER-nucleus signaling pathway	1
response to endoplasmic reticulum stress	1
cellular response to biotic stimulus	1
endoplasmic reticulum	1
intracellular calcium ion homeostasis	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
protein insertion into ER membrane	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
ribonucleoprotein complex binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
mitochondrion	1
mitochondrial envelope	1
ER membrane insertion complex	1

Protein interactions and networks

STRING

1296 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMCO1	CCDC47	Q96A33	787
TMCO1	GAS7	O60861	748
TMCO1	SIX6	O95475	720
TMCO1	MYOC	Q99972	697
TMCO1	CAV2	P51636	696
TMCO1	EMC3	Q9P0I2	690
TMCO1	WDR36	Q8NI36	628
TMCO1	SIX1	Q15475	620
TMCO1	AFAP1	Q8N556	617
TMCO1	SRBD1	Q8N5C6	613
TMCO1	GMDS	O60547	609
TMCO1	ATOH7	Q8N100	606
TMCO1	FNDC3B	Q53EP0	581
TMCO1	GET1	O00258	581
TMCO1	CAV1	Q03135	575

IntAct

121 interactions, top by confidence:

A	B	Type	Score
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
GPR17	IPO8	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
FAM177B	TMCO1	psi-mi:“MI:0915”(physical association)	0.400
KNL1	TMCO1	psi-mi:“MI:0915”(physical association)	0.400
KMT2A	TMCO1	psi-mi:“MI:0915”(physical association)	0.400
MPHOSPH9	TMCO1	psi-mi:“MI:0915”(physical association)	0.400
	DENR	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
MAPK6		psi-mi:“MI:0914”(association)	0.350
M	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
NS1	HAX1	psi-mi:“MI:0914”(association)	0.350
M2	ESYT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	TSPO	psi-mi:“MI:0914”(association)	0.350

BioGRID (256): ATP5F1 (Co-fractionation), CYC1 (Co-fractionation), HSD17B12 (Co-fractionation), PDHB (Co-fractionation), RAB1B (Co-fractionation), RPN1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation), TMCO1 (Co-fractionation)

ESM2 similar proteins: A0A8I3PI99, A0M8U1, A7Y521, B5DEN9, C5HGF3, O88544, O94973, P13666, P17427, P18484, P38024, Q00765, Q0VCK5, Q0X0A5, Q13098, Q1RLU8, Q28635, Q2PG42, Q3KNM2, Q3SZA0, Q3T0N3, Q3T126, Q3T178, Q3ZC24, Q4R5E6, Q5F418, Q5I0H4, Q5M7T4, Q5R648, Q5R9B0, Q5R9M4, Q5RE33, Q5ZJ41, Q5ZJD7, Q6DGW9, Q6GM44, Q6NRT5, Q7TQ48, Q8C407, Q8R1Z9

Diamond homologs: A0A8I3PI99, C5HGF3, Q19714, Q3T0N3, Q54TU8, Q5I0H4, Q5R9B0, Q6DGW9, Q921L3, Q9UM00

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 151 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
FCERI mediated MAPK activation	5	17.0×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytosolic calcium ion concentration	10	9.1×	2e-04
phospholipase C-activating G protein-coupled receptor signaling pathway	7	7.1×	1e-02
G protein-coupled receptor signaling pathway	16	4.5×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	6
Uncertain significance	27
Likely benign	22
Benign	15

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1696843	NM_019026.6(TMCO1):c.70G>C (p.Gly24Arg)	Pathogenic
189248	NM_019026.6(TMCO1):c.87_90del (p.Val30fs)	Pathogenic
218899	NM_019026.6(TMCO1):c.323+3G>C	Pathogenic
265628	NM_019026.6(TMCO1):c.187C>T (p.Arg63Ter)	Pathogenic
3248013	NC_000001.10:g.(?165697260)(165738141_?)del	Pathogenic
521850	NM_019026.6(TMCO1):c.372C>A (p.Tyr124Ter)	Pathogenic
521929	NM_019026.6(TMCO1):c.391C>T (p.Arg131Ter)	Pathogenic
88739	NM_019026.6(TMCO1):c.259C>T (p.Arg87Ter)	Pathogenic
1325197	NM_019026.6(TMCO1):c.-33del	Likely pathogenic
1331642	NM_019026.6(TMCO1):c.147dup (p.Leu50fs)	Likely pathogenic
1711875	NM_019026.6(TMCO1):c.70G>A (p.Gly24Ser)	Likely pathogenic
3780713	NM_019026.6(TMCO1):c.-54_-35dup	Likely pathogenic
4529723	NM_019026.6(TMCO1):c.71-2A>G	Likely pathogenic
598949	NM_019026.6(TMCO1):c.493_494del (p.Ala165fs)	Likely pathogenic

SpliceAI

1163 predictions. Top by Δscore:

Variant	Effect	Δscore
1:165743162:CTCA:C	donor_loss	1.0000
1:165743163:TCA:T	donor_loss	1.0000
1:165743165:A:AC	donor_gain	1.0000
1:165743165:ACC:A	donor_loss	1.0000
1:165743166:C:CC	donor_gain	1.0000
1:165743166:C:CG	donor_loss	1.0000
1:165743307:CAAAT:C	acceptor_gain	1.0000
1:165743311:TC:T	acceptor_loss	1.0000
1:165743312:C:CC	acceptor_gain	1.0000
1:165743312:CTAAA:C	acceptor_loss	1.0000
1:165743313:T:A	acceptor_loss	1.0000
1:165752095:CACT:C	donor_loss	1.0000
1:165752096:ACTC:A	donor_loss	1.0000
1:165752097:CTCA:C	donor_loss	1.0000
1:165752098:T:TA	donor_loss	1.0000
1:165752099:CAC:C	donor_loss	1.0000
1:165752100:A:AC	donor_gain	1.0000
1:165752100:A:T	donor_loss	1.0000
1:165752101:C:CA	donor_loss	1.0000
1:165752101:C:CC	donor_gain	1.0000
1:165752101:CATGG:C	donor_gain	1.0000
1:165752166:GAACC:G	acceptor_loss	1.0000
1:165752167:AACCT:A	acceptor_loss	1.0000
1:165752169:CCTG:C	acceptor_loss	1.0000
1:165752170:CTGT:C	acceptor_loss	1.0000
1:165752171:T:A	acceptor_loss	1.0000
1:165754226:A:AC	donor_gain	1.0000
1:165754226:AC:A	donor_gain	1.0000
1:165754227:C:CC	donor_gain	1.0000
1:165754227:C:CG	donor_loss	1.0000

AlphaMissense

1541 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:165743187:A:G	C201R	1.000
1:165743200:G:C	F196L	1.000
1:165743200:G:T	F196L	1.000
1:165743202:A:G	F196L	1.000
1:165743206:G:C	F194L	1.000
1:165743206:G:T	F194L	1.000
1:165743208:A:G	F194L	1.000
1:165743278:A:C	F170L	1.000
1:165743278:A:T	F170L	1.000
1:165743280:A:G	F170L	1.000
1:165743308:A:C	F160L	1.000
1:165743308:A:T	F160L	1.000
1:165743310:A:G	F160L	1.000
1:165743310:A:T	F160I	1.000
1:165752126:G:T	A151D	1.000
1:165752131:A:C	F149L	1.000
1:165752131:A:T	F149L	1.000
1:165752133:A:G	F149L	1.000
1:165752136:A:G	C148R	1.000
1:165752141:C:T	G146D	1.000
1:165752142:C:G	G146R	1.000
1:165752147:G:T	A144D	1.000
1:165754235:A:G	L134P	1.000
1:165754256:A:G	L127P	1.000
1:165768224:A:G	L90P	1.000
1:165728081:G:T	A221D	0.999
1:165728113:C:A	Q210H	0.999
1:165728113:C:G	Q210H	0.999
1:165743171:C:A	R206L	0.999
1:165743174:A:T	I205N	0.999

dbSNP variants (sampled 300 via entrez): RS1000184484 (1:165765776 G>C), RS1000281584 (1:165760634 T>A), RS1000341271 (1:165753421 C>G,T), RS1000406719 (1:165747196 G>A,C), RS1000436537 (1:165741107 C>T), RS1000515968 (1:165736423 A>C), RS1000692052 (1:165748571 T>C), RS1000723563 (1:165723994 G>T), RS1000748869 (1:165767252 T>C), RS1000789652 (1:165748841 C>T), RS1000836235 (1:165753658 T>A), RS1000842033 (1:165749154 C>T), RS1000912945 (1:165761854 T>A), RS1001032196 (1:165742695 A>G), RS1001089162 (1:165736081 G>A)

Disease associations

OMIM: gene MIM:614123 | disease phenotypes: MIM:213980

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebrofaciothoracic dysplasia	Definitive	Autosomal recessive
craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1	Definitive	Autosomal recessive

Mondo (2): craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 (MONDO:0800436), (MONDO:0008952)

Orphanet (1): Cerebrofaciothoracic dysplasia (Orphanet:1394)

HPO phenotypes

93 total (30 of 93 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000049	Shawl scrotum
HP:0000122	Unilateral renal agenesis
HP:0000154	Wide mouth
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000527	Long eyelashes

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST001062_1	Glaucoma	6.000000e-14
GCST001506_2	Intraocular pressure	2.000000e-08
GCST002168_3	Intraocular pressure	8.000000e-08
GCST002580_2	Intraocular pressure	2.000000e-09
GCST002582_7	Glaucoma (primary open-angle)	5.000000e-13
GCST004074_15	Intraocular pressure	2.000000e-12
GCST004074_16	Intraocular pressure	6.000000e-12
GCST005170_20	Intraocular pressure	7.000000e-30
GCST005170_4	Intraocular pressure	2.000000e-18
GCST005580_132	Intraocular pressure	4.000000e-45
GCST005580_133	Intraocular pressure	1.000000e-43
GCST006065_22	Glaucoma (primary open-angle)	2.000000e-62
GCST006066_1	Glaucoma (primary open-angle)	8.000000e-41
GCST006067_1	Glaucoma (primary open-angle)	8.000000e-44
GCST006394_31	Intraocular pressure	8.000000e-68
GCST006395_12	Glaucoma	2.000000e-52
GCST006395_32	Glaucoma	4.000000e-51
GCST006412_14	Intraocular pressure	2.000000e-87
GCST006412_26	Intraocular pressure	1.000000e-22
GCST007944_3	Medication use (antiglaucoma preparations and miotics)	1.000000e-39
GCST008319_1	Intraocular pressure (corneal compensated)	3.000000e-07
GCST009413_8	Intraocular pressure	2.000000e-11
GCST009722_20	Glaucoma (multi-trait analysis)	6.000000e-92
GCST009723_80	Vertical cup-disc ratio (adjusted for vertical disc diameter)	2.000000e-06
GCST009725_1	Intraocular pressure	4.000000e-67
GCST009726_30	Glaucoma	4.000000e-43
GCST010002_397	Refractive error	9.000000e-48
GCST011439_18	Glaucoma (primary open-angle)	2.000000e-32
GCST011441_2	Glaucoma (high intraocular pressure)	9.000000e-18
GCST90011766_1	Glaucoma (primary open-angle)	1.000000e-62

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0009944	Antiglaucoma preparations and miotics use measurement
EFO:0006939	cup-to-disc ratio measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565862	Cerebrofaciothoracic Dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067368 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.66	Kd	21.93	nM	CHEMBL3752910
7.66	ED50	21.93	nM	CHEMBL3752910
6.55	Kd	280.9	nM	CHEMBL5653589
6.55	ED50	280.9	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149600: Binding affinity to human TMCO1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0219	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149600: Binding affinity to human TMCO1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2809	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	3
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Rotenone	increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
beta-lapachone	decreases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Hydralazine	increases expression, affects cotreatment	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Cadmium Chloride	decreases expression, increases methylation	1
Particulate Matter	decreases expression, increases abundance	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
CHEMBL5652642	Binding	Binding affinity to human TMCO1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7HN	Ubigene HEK293T TMCO1 KO	Transformed cell line	Female
CVCL_E2M1	HAP1 TMCO1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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