TMEM138

Summary

TMEM138 (transmembrane protein 138, HGNC:26944) is a protein-coding gene on chromosome 11q12.2, encoding Transmembrane protein 138 (Q9NPI0). Required for ciliogenesis.

This gene encodes a multi-pass transmembrane protein. Reduced expression of this gene in mouse fibroblasts causes short cilia and failure of ciliogenesis. Expression of this gene is tightly coordinated with expression of the neighboring gene TMEM216. Mutations in this gene are associated with the autosomal recessive neurodevelopmental disorder Joubert Syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51524 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Joubert syndrome 16 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 198 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 45
• MANE Select transcript: NM_016464

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26944
Approved symbol	TMEM138
Name	transmembrane protein 138
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC196, JBTS16
Ensembl gene	ENSG00000149483
Ensembl biotype	protein_coding
OMIM	614459
Entrez	51524

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 17 protein_coding, 5 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000278826, ENST00000381787, ENST00000423772, ENST00000451389, ENST00000507563, ENST00000534963, ENST00000539776, ENST00000540194, ENST00000542946, ENST00000543594, ENST00000543833, ENST00000545420, ENST00000685597, ENST00000686820, ENST00000688279, ENST00000688430, ENST00000689076, ENST00000689882, ENST00000691720, ENST00000692219, ENST00000692667, ENST00000692785, ENST00000693557, ENST00000886939, ENST00000886940, ENST00000886941, ENST00000928756, ENST00000928757, ENST00000928758

RefSeq mRNA: 5 — MANE Select: NM_016464 NM_001330281, NM_001410997, NM_001410998, NM_001410999, NM_016464

CCDS: CCDS8005, CCDS81569, CCDS91482, CCDS91483, CCDS91484

Canonical transcript exons

ENST00000278826 — 5 exons

Exon	Start	End
ENSE00001668656	61362374	61362420
ENSE00003230076	61368597	61369509
ENSE00003556955	61364252	61364518
ENSE00003605567	61367923	61367998
ENSE00003693469	61366045	61366216

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 98.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.2171 / max 534.9725, expressed in 1819 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114571	37.7278	1818
114567	2.3424	1336
114566	1.2966	738
114570	0.5541	319
114568	0.1608	52
114569	0.1355	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.15	gold quality
right adrenal gland cortex	UBERON:0035827	98.05	gold quality
left adrenal gland	UBERON:0001234	97.94	gold quality
left adrenal gland cortex	UBERON:0035825	97.82	gold quality
adrenal cortex	UBERON:0001235	97.24	gold quality
adrenal gland	UBERON:0002369	97.08	gold quality
right uterine tube	UBERON:0001302	95.45	gold quality
right ovary	UBERON:0002118	95.38	gold quality
mucosa of transverse colon	UBERON:0004991	94.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.49	gold quality
left ovary	UBERON:0002119	94.32	gold quality
left uterine tube	UBERON:0001303	94.11	gold quality
stromal cell of endometrium	CL:0002255	93.95	gold quality
body of uterus	UBERON:0009853	93.78	gold quality
right coronary artery	UBERON:0001625	93.62	gold quality
granulocyte	CL:0000094	93.48	gold quality
endocervix	UBERON:0000458	93.03	gold quality
left coronary artery	UBERON:0001626	93.03	gold quality
smooth muscle tissue	UBERON:0001135	92.89	gold quality
thoracic aorta	UBERON:0001515	92.78	gold quality
ascending aorta	UBERON:0001496	92.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.70	gold quality
omental fat pad	UBERON:0010414	92.68	gold quality
bone marrow cell	CL:0002092	92.65	gold quality
peritoneum	UBERON:0002358	92.64	gold quality
colonic epithelium	UBERON:0000397	92.62	gold quality
right lobe of thyroid gland	UBERON:0001119	92.56	gold quality
metanephros cortex	UBERON:0010533	92.52	gold quality
descending thoracic aorta	UBERON:0002345	92.44	gold quality
spleen	UBERON:0002106	92.43	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	4.32
E-GEOD-137537	no	1163.25
E-ENAD-17	no	1022.73
E-CURD-135	no	950.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting TMEM138, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-6809-5P	99.13	68.45	1223

Literature-anchored findings (GeneRIF, showing 3)

• study reports that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable ciliopathy, Joubert syndrome; expression of the genes is mediated by a conserved regulatory element in the noncoding intergenic region (PMID:22282472)
• Here we present clinical and molecular characterization of the case of an Emirati boy with Joubert syndrome, probably resulting from a splice-site mutation in TMEM138 (PMID:28102635)
• Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis. (PMID:35394880)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem138	ENSDARG00000090543
mus_musculus	Tmem138	ENSMUSG00000024666
rattus_norvegicus		ENSRNOG00000080123
drosophila_melanogaster	CG13999	FBGN0031753
caenorhabditis_elegans		WBGENE00008643

Protein

Protein identifiers

Transmembrane protein 138 — Q9NPI0 (reviewed: Q9NPI0)

All UniProt accessions (9): Q9NPI0, A0A8I5KPN0, A0A8I5KS61, A0A8I5KUI6, A0A8I5KUS6, A0A8I5KVU7, A0A8I5KXM0, A0A8I5QKQ3, J3QSZ6

UniProt curated annotations — full annotation on UniProt →

Function. Required for ciliogenesis.

Subcellular location. Vacuole membrane. Cell projection. Cilium.

Disease relevance. Joubert syndrome 16 (JBTS16) [MIM:614465] An autosomal recessive disorder characterized by oculomotor apraxia, variable coloboma, and rare kidney involvement. Neuroradiologically, it is characterized by an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and polydactyly. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. TMEM138 and TMEM216 genes are adjacent and are aligned in a head-to-tail configuration. They share some cis regulatory region and display coordinated expression. Genes were joined by chromosomal rearrangement at the amphiboan to reptile evolutionary transition around 340 million years ago.

Similarity. Belongs to the TMEM138 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NPI0-1	1	yes
Q9NPI0-2	2
Q9NPI0-3	3

RefSeq proteins (5): NP_001317210, NP_001397926, NP_001397927, NP_001397928, NP_057548* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024133	TM_138	Family

Pfam: PF14935

UniProt features (13 total): transmembrane region 4, sequence variant 4, splice variant 3, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPI0-F1	86.42	0.51

Functional residue map

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

Glycosylation sites (1): 6

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 195 (showing top): GOCC_VACUOLAR_MEMBRANE, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_CILIUM_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, FISCHER_DREAM_TARGETS, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GCM_NF2, MARTINEZ_RESPONSE_TO_TRABECTEDIN_DN, GOBP_CELL_PROJECTION_ORGANIZATION, GOCC_CILIUM, SCGGAAGY_ELK1_02, GCM_USP6, WHITFIELD_CELL_CYCLE_G2_M, WHITFIELD_CELL_CYCLE_M_G1

GO Biological Process (2): cilium assembly (GO:0060271), cell projection organization (GO:0030030)

GO Molecular Function (0):

GO Cellular Component (6): vacuolar membrane (GO:0005774), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), vacuole (GO:0005773), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cellular component organization	1
vacuole	1
bounding membrane of organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM138	TMEM237	Q96Q45	782
TMEM138	TMEM231	Q9H6L2	769
TMEM138	NPHP1	O15259	728
TMEM138	CPLANE1	Q9H799	720
TMEM138	TMEM216	Q9P0N5	714
TMEM138	TCTN3	Q6NUS6	713
TMEM138	MKS1	Q9NXB0	708
TMEM138	TMEM67	Q5HYA8	668
TMEM138	CC2D2A	Q9P2K1	667
TMEM138	CEP41	Q9BYV8	662
TMEM138	TCTN2	Q96GX1	644
TMEM138	TCTN1	Q2MV58	624
TMEM138	B9D1	Q9UPM9	621
TMEM138	RPGRIP1L	Q68CZ1	621
TMEM138	AHI1	Q8N157	600

IntAct

2 interactions, top by confidence:

A	B	Type	Score
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (7): TMEM138 (Proximity Label-MS), TMEM138 (Affinity Capture-RNA), TMEM138 (Affinity Capture-MS), TMEM138 (Affinity Capture-MS), TMEM138 (Affinity Capture-RNA), TMEM138 (Affinity Capture-RNA), TMEM138 (Affinity Capture-RNA)

ESM2 similar proteins: A0JNG0, A2A6H3, A3EXA0, A5PJY4, B1WBM3, C9JQI7, O00237, O74447, P04135, P09175, P0CX12, P0CX13, P24412, P33464, P36034, P36299, P47187, P52924, P53053, P69603, P69604, P69605, P69606, P69607, Q07788, Q0Q4E7, Q197D8, Q1LUD1, Q4V7Q8, Q5HZQ9, Q5MNV8, Q5PQM0, Q5PQN2, Q5RD28, Q63HM2, Q6ZFZ4, Q7ZY86, Q8R079, Q8RVL1, Q8RVL2

Diamond homologs: A5PJY4, B1WBM3, E7FDE0, Q66JC0, Q9D6G5, Q9NPI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	90
Likely benign	62
Benign	9

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1424816	NM_016464.5(TMEM138):c.83del (p.Phe27_Ser28insTer)	Pathogenic
1458178	NM_016464.5(TMEM138):c.94C>T (p.Gln32Ter)	Pathogenic
1460234	NC_000011.9:g.(?61133497)(61133708_?)del	Pathogenic
1982443	NM_016464.5(TMEM138):c.311G>A (p.Trp104Ter)	Pathogenic
2018227	NM_016464.5(TMEM138):c.306dup (p.Arg103fs)	Pathogenic
31190	NM_016464.5(TMEM138):c.376G>A (p.Ala126Thr)	Pathogenic
3686760	NM_016464.5(TMEM138):c.293G>A (p.Trp98Ter)	Pathogenic
917959	NM_016464.5(TMEM138):c.377-3C>G	Pathogenic
2498514	NM_016464.5(TMEM138):c.66_69del (p.Phe23fs)	Likely pathogenic
2501221	NC_000011.9:g.(61131991_61133516)_(61133689_61135394)del	Likely pathogenic
266092	NM_016464.5(TMEM138):c.134A>G (p.Gln45Arg)	Likely pathogenic
3599797	NM_016464.5(TMEM138):c.37del (p.Leu13fs)	Likely pathogenic
3599801	NM_016464.5(TMEM138):c.128+2T>G	Likely pathogenic
3691403	NM_016464.5(TMEM138):c.300+1G>T	Likely pathogenic
4278416	NM_016464.5(TMEM138):c.97_98del (p.Lys33fs)	Likely pathogenic

SpliceAI

992 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61364523:GTGCA:G	donor_gain	1.0000
11:61364525:GCA:G	donor_gain	1.0000
11:61364528:G:GG	donor_gain	1.0000
11:61364542:A:T	donor_gain	1.0000
11:61366036:T:G	acceptor_gain	1.0000
11:61366043:A:AG	acceptor_gain	1.0000
11:61366044:G:GG	acceptor_gain	1.0000
11:61366044:GC:G	acceptor_gain	1.0000
11:61366143:A:AG	donor_gain	1.0000
11:61362016:C:CA	donor_gain	0.9900
11:61362024:T:TA	donor_gain	0.9900
11:61362418:G:GT	donor_gain	0.9900
11:61362421:GTGA:G	donor_loss	0.9900
11:61362422:T:G	donor_loss	0.9900
11:61364387:G:GT	donor_gain	0.9900
11:61364399:GACCA:G	donor_gain	0.9900
11:61364404:G:GG	donor_gain	0.9900
11:61364519:G:GG	donor_gain	0.9900
11:61364576:GTG:G	donor_gain	0.9900
11:61366040:TACA:T	acceptor_loss	0.9900
11:61366042:C:G	acceptor_gain	0.9900
11:61366042:CAG:C	acceptor_loss	0.9900
11:61366043:A:C	acceptor_loss	0.9900
11:61366173:C:G	donor_gain	0.9900
11:61366213:CATG:C	donor_loss	0.9900
11:61366214:ATGGT:A	donor_loss	0.9900
11:61366215:TGG:T	donor_loss	0.9900
11:61366217:GTAA:G	donor_loss	0.9900
11:61366218:T:A	donor_loss	0.9900
11:61367921:A:AG	acceptor_gain	0.9900

AlphaMissense

1072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61366190:A:C	S92R	0.938
11:61366192:C:A	S92R	0.938
11:61366192:C:G	S92R	0.938
11:61366148:T:C	F78L	0.922
11:61366150:C:A	F78L	0.922
11:61366150:C:G	F78L	0.922
11:61366112:T:C	F66L	0.914
11:61366114:C:A	F66L	0.914
11:61366114:C:G	F66L	0.914
11:61368625:A:C	K135N	0.896
11:61368625:A:T	K135N	0.896
11:61366106:T:C	F64L	0.873
11:61366108:C:A	F64L	0.873
11:61366108:C:G	F64L	0.873
11:61364514:T:C	F42L	0.871
11:61364516:C:A	F42L	0.871
11:61364516:C:G	F42L	0.871
11:61367980:T:C	F120L	0.860
11:61367982:T:A	F120L	0.860
11:61367982:T:G	F120L	0.860
11:61364465:T:A	N25K	0.832
11:61364465:T:G	N25K	0.832
11:61367994:A:C	R124S	0.802
11:61367994:A:T	R124S	0.802
11:61364469:T:C	F27L	0.798
11:61364471:C:A	F27L	0.798
11:61364471:C:G	F27L	0.798
11:61366097:T:C	F61L	0.798
11:61366099:C:A	F61L	0.798
11:61366099:C:G	F61L	0.798

dbSNP variants (sampled 300 via entrez): RS1000105849 (11:61363993 C>G), RS1000147030 (11:61376982 A>G), RS1000624615 (11:61364307 C>A,T), RS1000890866 (11:61365570 AT>A,ATT), RS1000923142 (11:61368701 C>G,T), RS1001037181 (11:61368998 G>A,T), RS1001267982 (11:61375826 C>T), RS1001364006 (11:61376916 G>A,T), RS1001554190 (11:61363359 A>G), RS1001606679 (11:61363009 G>C), RS1001942281 (11:61370477 G>A), RS1002165407 (11:61364565 A>C,T), RS1002248936 (11:61375057 G>A), RS1002363527 (11:61375447 C>G), RS1002500617 (11:61362705 A>G)

Disease associations

OMIM: gene MIM:614459 | disease phenotypes: MIM:614465, MIM:249000

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 16	Strong	Autosomal recessive
Joubert syndrome with oculorenal defect	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy	Moderate	AR

Mondo (4): Joubert syndrome 16 (MONDO:0013764), Joubert syndrome and related disorders (MONDO:0015369), Meckel syndrome (MONDO:0018921), Joubert syndrome with oculorenal defect (MONDO:0009480)

Orphanet (3): Joubert syndrome with oculorenal defect (Orphanet:2318), Joubert syndrome and related disorders (Orphanet:140874), Meckel syndrome (Orphanet:564)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000090	Nephronophthisis
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000556	Retinal dystrophy
HP:0000567	Chorioretinal coloboma
HP:0000589	Coloboma
HP:0000612	Iris coloboma
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537430	Arima syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	increases methylation, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
afuresertib	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
monomethylarsonous acid	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Flame Retardants	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Smoke	increases abundance, increases expression	1
Thiram	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases expression, increases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study