TMEM218

Summary

TMEM218 (transmembrane protein 218, HGNC:27344) is a protein-coding gene on chromosome 11q24.2, encoding Transmembrane protein 218 (A2RU14). May be involved in ciliary biogenesis or function.

Predicted to be located in cilium and membrane. Implicated in Joubert syndrome.

Source: NCBI Gene 219854 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Joubert syndrome 39 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 35 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 49
• MANE Select transcript: NM_001258244

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27344
Approved symbol	TMEM218
Name	transmembrane protein 218
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000150433
Ensembl biotype	protein_coding
OMIM	619285
Entrez	219854

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 62 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000279968, ENST00000524373, ENST00000526175, ENST00000527257, ENST00000527271, ENST00000527766, ENST00000528724, ENST00000529530, ENST00000529583, ENST00000529609, ENST00000531262, ENST00000531851, ENST00000531909, ENST00000532156, ENST00000532407, ENST00000532717, ENST00000533273, ENST00000682305, ENST00000851942, ENST00000851943, ENST00000851944, ENST00000851945, ENST00000851946, ENST00000851947, ENST00000851948, ENST00000851949, ENST00000851950, ENST00000851951, ENST00000851952, ENST00000851953, ENST00000851954, ENST00000851955, ENST00000851956, ENST00000851957, ENST00000851958, ENST00000851959, ENST00000851960, ENST00000851961, ENST00000851962, ENST00000851963, ENST00000851964, ENST00000851965, ENST00000851966, ENST00000851967, ENST00000851968, ENST00000851969, ENST00000930988, ENST00000930989, ENST00000930990, ENST00000930991, ENST00000930992, ENST00000930993, ENST00000930994, ENST00000930995, ENST00000930996, ENST00000930997, ENST00000930998, ENST00000930999, ENST00000931000, ENST00000931001, ENST00000931002, ENST00000931003, ENST00000931004, ENST00000941462, ENST00000941463, ENST00000941464

RefSeq mRNA: 40 — MANE Select: NM_001258244 NM_001080546, NM_001258238, NM_001258239, NM_001258240, NM_001258241, NM_001258242, NM_001258243, NM_001258244, NM_001258245, NM_001258246, NM_001258247, NM_001387230, NM_001387231, NM_001387232, NM_001387233, NM_001387234, NM_001387235, NM_001387236, NM_001387237, NM_001387238, NM_001387239, NM_001387240, NM_001387241, NM_001387242, NM_001387244, NM_001387245, NM_001387246, NM_001387247, NM_001387248, NM_001387249, NM_001387250, NM_001387251, NM_001387252, NM_001387253, NM_001387254, NM_001387255, NM_001387256, NM_001387257, NM_001387258, NM_001387259

CCDS: CCDS31715, CCDS91617

Canonical transcript exons

ENST00000682305 — 5 exons

Exon	Start	End
ENSE00000994877	125102132	125102317
ENSE00002173028	125102734	125102809
ENSE00003554142	125101201	125101303
ENSE00003916987	125094389	125097740
ENSE00003921065	125111539	125111626

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 92.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8357 / max 97.5973, expressed in 1785 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122983	8.1782	1778
122984	0.6575	366

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	92.70	gold quality
ventricular zone	UBERON:0003053	92.12	gold quality
monocyte	CL:0000576	91.56	gold quality
leukocyte	CL:0000738	91.32	gold quality
right adrenal gland	UBERON:0001233	90.64	gold quality
right adrenal gland cortex	UBERON:0035827	90.49	gold quality
left adrenal gland	UBERON:0001234	89.70	gold quality
left adrenal gland cortex	UBERON:0035825	89.63	gold quality
smooth muscle tissue	UBERON:0001135	89.42	gold quality
body of pancreas	UBERON:0001150	89.33	gold quality
oocyte	CL:0000023	89.31	gold quality
endocervix	UBERON:0000458	89.24	gold quality
ileal mucosa	UBERON:0000331	89.22	gold quality
embryo	UBERON:0000922	89.20	gold quality
ganglionic eminence	UBERON:0004023	89.20	gold quality
upper arm skin	UBERON:0004263	89.16	silver quality
adrenal cortex	UBERON:0001235	89.09	gold quality
body of uterus	UBERON:0009853	88.93	gold quality
granulocyte	CL:0000094	88.82	gold quality
islet of Langerhans	UBERON:0000006	88.73	gold quality
right ovary	UBERON:0002118	88.52	gold quality
pancreas	UBERON:0001264	88.51	gold quality
calcaneal tendon	UBERON:0003701	88.51	gold quality
adrenal gland	UBERON:0002369	88.46	gold quality
fallopian tube	UBERON:0003889	88.38	gold quality
left coronary artery	UBERON:0001626	88.33	gold quality
ectocervix	UBERON:0012249	88.29	gold quality
left ovary	UBERON:0002119	88.04	gold quality
spleen	UBERON:0002106	87.91	gold quality
right coronary artery	UBERON:0001625	87.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

102 targeting TMEM218, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4495	99.82	72.08	3080

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem218	ENSDARG00000027129
mus_musculus	Tmem218	ENSMUSG00000032121
rattus_norvegicus	Tmem218	ENSRNOG00000008757

Protein

Protein identifiers

Transmembrane protein 218 — A2RU14 (reviewed: A2RU14)

All UniProt accessions (5): A2RU14, B7ZM54, E9PI23, E9PL96, E9PQM6

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in ciliary biogenesis or function.

Subunit / interactions. Interacts with TMEM67.

Subcellular location. Membrane. Cell projection. Cilium.

Disease relevance. TMEM218 mutations result in ciliary dysfunction leading to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and nephronophtisis among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome influence the clinical outcome. Joubert syndrome 39 (JBTS39) [MIM:619562] A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS39 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TMEM218 family.

RefSeq proteins (40): NP_001074015, NP_001245167, NP_001245168, NP_001245169, NP_001245170, NP_001245171, NP_001245172, NP_001245173, NP_001245174, NP_001245175, NP_001245176, NP_001374159, NP_001374160, NP_001374161, NP_001374162, NP_001374163, NP_001374164, NP_001374165, NP_001374166, NP_001374167, NP_001374168, NP_001374169, NP_001374170, NP_001374171, NP_001374173, NP_001374174, NP_001374175, NP_001374176, NP_001374177, NP_001374178, NP_001374179, NP_001374180, NP_001374181, NP_001374182, NP_001374183, NP_001374184, NP_001374185, NP_001374186, NP_001374187, NP_001374188 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026771	Tmem218	Family
IPR057973	TMEM218_N	Domain

Pfam: PF25810

UniProt features (9 total): sequence variant 5, transmembrane region 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A2RU14-F1	87.79	0.49

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 195 (showing top): LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, DURCHDEWALD_SKIN_CARCINOGENESIS_UP, NUYTTEN_EZH2_TARGETS_DN, GOCC_CILIUM, chr11q24, GINESTIER_BREAST_CANCER_20Q13_AMPLIFICATION_UP, YAMANAKA_GLIOBLASTOMA_SURVIVAL_DN, KRIEG_KDM3A_TARGETS_NOT_HYPOXIA, CRX_DN.V1_UP, ASH1L_TARGET_GENES, BARX1_TARGET_GENES, CEBPZ_TARGET_GENES, HOXB6_TARGET_GENES, MAFG_TARGET_GENES

GO Biological Process (0):

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

GO Cellular Component (3): cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
binding	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM218	TMEM17	Q86X19	717
TMEM218	TMEM231	Q9H6L2	674
TMEM218	B9D1	Q9UPM9	665
TMEM218	B9D2	Q9BPU9	660
TMEM218	MKS1	Q9NXB0	610
TMEM218	TMEM216	Q9P0N5	605
TMEM218	TMEM67	Q5HYA8	599
TMEM218	TMEM107	Q6UX40	595
TMEM218	CC2D2A	Q9P2K1	591
TMEM218	RPGRIP1L	Q68CZ1	573
TMEM218	WBP1	Q96G27	560
TMEM218	TMEM237	Q96Q45	514
TMEM218	OGFOD2	Q6N063	509
TMEM218	MFRP	Q9BY79	479
TMEM218	MOB3C	Q70IA8	466

IntAct

229 interactions, top by confidence:

A	B	Type	Score
LDLRAD1	TMEM218	psi-mi:“MI:0915”(physical association)	0.830
TMEM218	LDLRAD1	psi-mi:“MI:0915”(physical association)	0.830
CREB3L1	TMEM218	psi-mi:“MI:0915”(physical association)	0.780
TMEM218	CREB3L1	psi-mi:“MI:0915”(physical association)	0.780
PCNA	TMEM218	psi-mi:“MI:0915”(physical association)	0.670
TMEM218	PCNA	psi-mi:“MI:0915”(physical association)	0.670
TMEM218	TMEM45B	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	SLC10A4	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	TMEM234	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	CPLX4	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	SLC18A1	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	IFNGR2	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (83): TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), LDLRAD1 (Two-hybrid), TMEM218 (Two-hybrid), PCNA (Two-hybrid), CREB3L1 (Two-hybrid), LDLRAD1 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid), TMEM218 (Two-hybrid)

ESM2 similar proteins: A2C127, A2RU14, A5PJF4, B1XIE1, B2JA13, B8HTR1, D3Z338, O28147, O28148, O28149, O28517, O28688, O28817, O29981, O30088, O30278, O66959, O83486, P04123, P07503, P0DXB3, P18034, P20200, P51769, P53089, P75346, P76692, P80101, P80107, Q0IDF4, Q10XU6, Q36907, Q3E7B6, Q46LY0, Q54J38, Q57788, Q5U3Y9, Q5WG37, Q6ENR2, Q6L3F1

Diamond homologs: A2RU14, A5PJF4, B0JYX6, Q5U3Y9, Q7SZ56, Q9CQ44

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	18
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
983528	NM_001258244.2(TMEM218):c.26G>T (p.Gly9Val)	Pathogenic
983529	NM_001258244.2(TMEM218):c.175C>T (p.Arg59Ter)	Pathogenic
1677283	NM_001258244.2(TMEM218):c.111G>T (p.Arg37Ser)	Likely pathogenic
983527	NM_001258244.2(TMEM218):c.238C>T (p.Arg80Cys)	Likely pathogenic

SpliceAI

738 predictions. Top by Δscore:

Variant	Effect	Δscore
11:125101278:C:CT	acceptor_gain	1.0000
11:125101279:G:T	acceptor_gain	1.0000
11:125111584:CACCT:C	donor_gain	1.0000
11:125097737:CAAT:C	acceptor_gain	0.9900
11:125101205:A:C	donor_gain	0.9900
11:125101380:T:TA	donor_gain	0.9900
11:125111583:A:AC	donor_gain	0.9900
11:125111583:ACAC:A	donor_gain	0.9900
11:125111584:C:CC	donor_gain	0.9900
11:125111584:CA:C	donor_gain	0.9900
11:125111584:CACC:C	donor_gain	0.9900
11:125097738:AATC:A	acceptor_loss	0.9800
11:125097739:ATCT:A	acceptor_loss	0.9800
11:125097740:TCT:T	acceptor_loss	0.9800
11:125097741:C:CC	acceptor_gain	0.9800
11:125097741:CTGG:C	acceptor_loss	0.9800
11:125097742:T:A	acceptor_loss	0.9800
11:125101208:T:TA	donor_gain	0.9800
11:125101409:C:A	donor_gain	0.9800
11:125102322:C:T	acceptor_gain	0.9800
11:125101195:CTTTA:C	donor_loss	0.9700
11:125101196:TTTAC:T	donor_loss	0.9700
11:125101197:TTACC:T	donor_loss	0.9700
11:125101198:TA:T	donor_loss	0.9700
11:125101199:A:C	donor_loss	0.9700
11:125101200:C:T	donor_loss	0.9700
11:125101284:A:AC	acceptor_gain	0.9700
11:125102321:CCG:C	acceptor_gain	0.9700
11:125102322:C:CT	acceptor_gain	0.9700
11:125110742:AAGC:A	donor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000144609 (11:125098319 G>A,C), RS1000608702 (11:125096500 A>C,G), RS1000713991 (11:125102729 C>T), RS1000743194 (11:125109915 T>G), RS1000768039 (11:125102422 T>C), RS1001033405 (11:125103162 A>G), RS1001062850 (11:125096294 C>A), RS1001139903 (11:125096740 G>T), RS1001642111 (11:125102022 C>T), RS1001668529 (11:125094796 T>C,G), RS1001708348 (11:125107204 T>C), RS1001767214 (11:125100954 G>T), RS1002009601 (11:125101772 A>G), RS1002009617 (11:125095092 G>A), RS1002420702 (11:125112036 G>T)

Disease associations

OMIM: gene MIM:619285 | disease phenotypes: MIM:619562, MIM:213300, MIM:611134

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 39	Strong	Autosomal recessive
ciliopathy	Strong	Autosomal recessive

Mondo (4): Joubert syndrome 39 (MONDO:0030454), Joubert syndrome (MONDO:0018772), Meckel syndrome, type 4 (MONDO:0012626), ciliopathy (MONDO:0005308)

Orphanet (2): Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000113	Polycystic kidney dysplasia
HP:0000202	Orofacial cleft
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000556	Retinal dystrophy
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0001161	Hand polydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001320	Cerebellar vermis hypoplasia
HP:0001337	Tremor
HP:0001696	Situs inversus totalis
HP:0001829	Foot polydactyly
HP:0002084	Encephalocele
HP:0002085	Occipital encephalocele
HP:0002104	Apnea
HP:0002126	Polymicrogyria

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002861_2	Breast cancer (survival)	1.000000e-09
GCST006087_1	Familial lung adenocarcinoma	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time
EFO:0006953	family history of lung cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, decreases expression	3
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
potassium chromate(VI)	decreases expression	1
mercuric bromide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
entinostat	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Panobinostat	decreases expression	1
Arsenic	affects methylation	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Formaldehyde	decreases expression	1
Gallic Acid	decreases expression	1
Phenylmercuric Acetate	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
p-Chloromercuribenzoic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study