TMEM38A

Summary

TMEM38A (transmembrane protein 38A, HGNC:28462) is a protein-coding gene on chromosome 19p13.11, encoding Trimeric intracellular cation channel type A (Q9H6F2). Intracellular monovalent cation channel required for maintenance of rapid intracellular calcium release.

Predicted to enable potassium channel activity. Predicted to be involved in regulation of release of sequestered calcium ion into cytosol. Predicted to act upstream of or within several processes, including cellular response to caffeine; monoatomic cation transmembrane transport; and regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion. Located in extracellular exosome.

Source: NCBI Gene 79041 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_024074

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28462
Approved symbol	TMEM38A
Name	transmembrane protein 38A
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC3169, TRIC-A
Ensembl gene	ENSG00000072954
Ensembl biotype	protein_coding
OMIM	611235
Entrez	79041

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000187762, ENST00000595452, ENST00000599479, ENST00000886247, ENST00000886248, ENST00000926885, ENST00000953901

RefSeq mRNA: 1 — MANE Select: NM_024074 NM_024074

CCDS: CCDS12349

Canonical transcript exons

ENST00000187762 — 6 exons

Exon	Start	End
ENSE00000687208	16680397	16680581
ENSE00000687210	16682421	16682508
ENSE00000687213	16686288	16686405
ENSE00001129813	16661139	16661341
ENSE00001309146	16688144	16690023
ENSE00003569987	16679984	16680140

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.1522 / max 234.8794, expressed in 1031 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174437	4.1522	1031

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.49	gold quality
gastrocnemius	UBERON:0001388	98.29	gold quality
quadriceps femoris	UBERON:0001377	97.97	gold quality
vastus lateralis	UBERON:0001379	97.78	gold quality
skeletal muscle tissue	UBERON:0001134	97.73	gold quality
tibialis anterior	UBERON:0001385	97.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.64	gold quality
skeletal muscle organ	UBERON:0014892	97.32	gold quality
muscle of leg	UBERON:0001383	97.20	gold quality
deltoid	UBERON:0001476	96.85	gold quality
biceps brachii	UBERON:0001507	96.67	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.22	gold quality
body of tongue	UBERON:0011876	94.71	gold quality
muscle tissue	UBERON:0002385	92.68	gold quality
prefrontal cortex	UBERON:0000451	89.85	gold quality
right frontal lobe	UBERON:0002810	89.55	gold quality
putamen	UBERON:0001874	87.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.80	gold quality
tongue	UBERON:0001723	87.42	gold quality
heart left ventricle	UBERON:0002084	87.33	gold quality
apex of heart	UBERON:0002098	87.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.04	gold quality
frontal cortex	UBERON:0001870	86.99	gold quality
cardiac ventricle	UBERON:0002082	86.98	gold quality
caudate nucleus	UBERON:0001873	86.84	gold quality
middle temporal gyrus	UBERON:0002771	85.85	gold quality
neocortex	UBERON:0001950	85.80	gold quality
nucleus accumbens	UBERON:0001882	85.74	gold quality
primary visual cortex	UBERON:0002436	85.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting TMEM38A, 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-1252-5P	100.00	69.80	2774
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-5189-3P	97.52	66.33	487
HSA-MIR-6807-5P	97.51	64.25	1046
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-4794	96.47	65.53	1063
HSA-MIR-664A-5P	95.84	64.93	949
HSA-MIR-4524B-3P	95.52	64.12	964
HSA-MIR-6890-5P	92.89	65.83	442

Literature-anchored findings (GeneRIF, showing 2)

• TRIC-A is a negative regulator of STIM1/Orai1 function.TRIC-A interacts with STIM1 and coclusters at endoplasmic reticulum-plasma membrane junctions. (PMID:32330125)
• Exploring a novel seven-gene marker and mitochondrial gene TMEM38A for predicting cervical cancer radiotherapy sensitivity using machine learning algorithms. (PMID:38327905)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem38a	ENSDARG00000024047
mus_musculus	Tmem38a	ENSMUSG00000031791
rattus_norvegicus	Tmem38a	ENSRNOG00000011912
drosophila_melanogaster	CG4239	FBGN0030745
caenorhabditis_elegans		WBGENE00013255
caenorhabditis_elegans		WBGENE00013268

Paralogs (1): TMEM38B (ENSG00000095209)

Protein

Protein identifiers

Trimeric intracellular cation channel type A — Q9H6F2 (reviewed: Q9H6F2)

Alternative names: Transmembrane protein 38A

All UniProt accessions (2): Q9H6F2, M0QYB6

UniProt curated annotations — full annotation on UniProt →

Function. Intracellular monovalent cation channel required for maintenance of rapid intracellular calcium release. Acts as a potassium counter-ion channel that functions in synchronization with calcium release from intracellular stores. Opened by a change of voltage within the sarcoplasmic reticulum lumen.

Subunit / interactions. Homotrimer; conformation seems to be controled by binding to diacylglycerol (DAG).

Subcellular location. Sarcoplasmic reticulum membrane. Nucleus membrane.

Activity regulation. Channel activity is activated by a change of voltage within the sarcoplasmic reticulum lumen and blocked by luminal high Ca(2+) levels.

Similarity. Belongs to the TMEM38 family.

RefSeq proteins (1): NP_076979* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007866	TRIC_channel	Family

Pfam: PF05197

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (21 total): topological domain 8, transmembrane region 7, binding site 3, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6F2-F1	81.55	0.55

Functional residue map

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

Ligand- & substrate-binding residues (3): 74; 122; 126

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CIRCULATORY_SYSTEM_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, AREB6_01, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_RESPONSE_TO_ALKALOID, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_CALCIUM_ION_SIGNALING

GO Biological Process (10): endoplasmic reticulum organization (GO:0007029), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), regulation of release of sequestered calcium ion into cytosol (GO:0051279), cellular response to caffeine (GO:0071313), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220), potassium ion transmembrane transport (GO:0071805), obsolete inorganic cation transmembrane transport (GO:0098662)

GO Molecular Function (3): potassium channel activity (GO:0005267), identical protein binding (GO:0042802), metal ion binding (GO:0046872)

GO Cellular Component (6): nuclear membrane (GO:0031965), sarcoplasmic reticulum membrane (GO:0033017), extracellular exosome (GO:0070062), nucleus (GO:0005634), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
organelle organization	1
endomembrane system organization	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
release of sequestered calcium ion into cytosol	1
regulation of calcium ion transmembrane transport	1
response to caffeine	1
cellular response to alkaloid	1
cellular response to purine-containing compound	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
protein binding	1
cation binding	1
nucleus	1
nuclear envelope	1
organelle membrane	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
bounding membrane of organelle	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
endoplasmic reticulum	1
sarcoplasm	1

Protein interactions and networks

STRING

806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM38A	PLPP7	Q8NBV4	707
TMEM38A	SMIM7	Q9BQ49	669
TMEM38A	TMEM214	Q6NUQ4	631
TMEM38A	TMEM70	Q9BUB7	593
TMEM38A	TMEM154	Q6P9G4	579
TMEM38A	M0QYU9	M0QYU9	572
TMEM38A	WFS1	O76024	569
TMEM38A	SUN2	Q9UH99	547
TMEM38A	KLHL31	Q9H511	542
TMEM38A	DPPA2	Q7Z7J5	532
TMEM38A	TMEM201	Q5SNT2	517
TMEM38A	DHRS7	Q9Y394	515
TMEM38A	TMEM161A	Q9NX61	506
TMEM38A	SYTL3	Q4VX76	494
TMEM38A	POPDC2	Q9HBU9	490

IntAct

5 interactions, top by confidence:

A	B	Type	Score
HSD3B2	NARS1	psi-mi:“MI:0914”(association)	0.530
TMEM38A	DOK2	psi-mi:“MI:0914”(association)	0.530

BioGRID (18): ARRB2 (Affinity Capture-MS), NCEH1 (Affinity Capture-MS), PCP2 (Affinity Capture-MS), DOK2 (Affinity Capture-MS), TMEM38A (Affinity Capture-MS), OXLD1 (Affinity Capture-MS), NCEH1 (Affinity Capture-MS), PCP2 (Affinity Capture-MS), DOK2 (Affinity Capture-MS), LZTFL1 (Affinity Capture-MS), TMEM38A (Affinity Capture-RNA), TMEM38A (Affinity Capture-RNA), TMEM38A (Affinity Capture-MS), NCEH1 (Affinity Capture-MS), LZTFL1 (Affinity Capture-MS)

ESM2 similar proteins: A2AF53, A4FV75, A4K2N5, A4K2W1, A5A6S6, A6QL84, A6ZIQ8, A9JRA0, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O60337, P58749, Q08DE2, Q108U3, Q2TBU2, Q3SYY9, Q3TMP8, Q4R5E3, Q58DA4, Q5BJW3, Q5JZQ8, Q5R8H8, Q5R9W1, Q5RBJ7, Q5RFE0, Q5ZII3, Q62302, Q6UWH6, Q6ZQ89, Q78S06, Q7SYC7, Q7ZUA6, Q86W33, Q8CIF6, Q8K0B2, Q8N2H4, Q8NBJ9, Q8NFB2

Diamond homologs: A4FV75, A5A6S6, A6ZIQ8, Q0VC58, Q28FA9, Q3KQE5, Q3TMP8, Q5ZK43, Q68FV1, Q6GN30, Q6P2T0, Q6P8F8, Q7ZVP8, Q7ZY07, Q9DAV9, Q9H6F2, Q9NA73, Q9NA75, Q9NVV0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1162 predictions. Top by Δscore:

Variant	Effect	Δscore
19:16661331:G:GG	donor_gain	1.0000
19:16661337:GCCAG:G	donor_gain	1.0000
19:16661343:T:A	donor_loss	1.0000
19:16680136:GTCTG:G	donor_gain	1.0000
19:16680137:TCTGG:T	donor_loss	1.0000
19:16680138:CTGG:C	donor_loss	1.0000
19:16680139:TGGT:T	donor_loss	1.0000
19:16680140:GGTAA:G	donor_loss	1.0000
19:16680141:G:GG	donor_gain	1.0000
19:16680142:T:G	donor_loss	1.0000
19:16680394:AAGG:A	acceptor_loss	1.0000
19:16680420:T:TA	acceptor_gain	1.0000
19:16686286:A:AG	acceptor_gain	1.0000
19:16686287:G:GG	acceptor_gain	1.0000
19:16679979:CCCA:C	acceptor_loss	0.9900
19:16679981:CAG:C	acceptor_loss	0.9900
19:16679982:A:AG	acceptor_gain	0.9900
19:16679983:G:C	acceptor_loss	0.9900
19:16679983:G:GA	acceptor_gain	0.9900
19:16679983:GGA:G	acceptor_gain	0.9900
19:16680137:TCTG:T	donor_gain	0.9900
19:16680139:TG:T	donor_gain	0.9900
19:16680140:GG:G	donor_gain	0.9900
19:16680392:A:AG	acceptor_gain	0.9900
19:16680392:AAAAG:A	acceptor_gain	0.9900
19:16680421:G:A	acceptor_gain	0.9900
19:16680435:A:G	acceptor_gain	0.9900
19:16680482:G:GT	donor_gain	0.9900
19:16680487:G:GA	donor_gain	0.9900
19:16680548:T:TA	donor_gain	0.9900

AlphaMissense

1963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:16680022:T:A	W55R	0.999
19:16680022:T:C	W55R	0.999
19:16680139:T:A	W94R	0.999
19:16680139:T:C	W94R	0.999
19:16680569:G:T	G152W	0.999
19:16686301:A:C	S190R	0.999
19:16686303:C:A	S190R	0.999
19:16686303:C:G	S190R	0.999
19:16661299:A:C	S28R	0.998
19:16661301:T:A	S28R	0.998
19:16661301:T:G	S28R	0.998
19:16680052:A:C	S65R	0.998
19:16680054:C:A	S65R	0.998
19:16680054:C:G	S65R	0.998
19:16680569:G:A	G152R	0.998
19:16680569:G:C	G152R	0.998
19:16680570:G:A	G152E	0.998
19:16680581:G:C	G156R	0.998
19:16686311:G:A	G193E	0.998
19:16680045:C:G	C62W	0.997
19:16680481:G:C	K122N	0.997
19:16680481:G:T	K122N	0.997
19:16680482:G:A	E123K	0.997
19:16680483:A:T	E123V	0.997
19:16680492:G:C	R126P	0.997
19:16680512:G:C	G133R	0.997
19:16680572:T:A	W153R	0.997
19:16680572:T:C	W153R	0.997
19:16682421:G:A	G156D	0.997
19:16686310:G:A	G193R	0.997

dbSNP variants (sampled 300 via entrez): RS1000013406 (19:16685032 G>T), RS1000135279 (19:16662033 C>G,T), RS1000326145 (19:16689835 G>A,T), RS1000402060 (19:16661759 G>A), RS1000440752 (19:16690186 C>T), RS1000445827 (19:16663855 C>T), RS1000480554 (19:16689996 G>C), RS1000492135 (19:16690435 T>C), RS1000820926 (19:16684969 A>T), RS1000937911 (19:16679079 G>A,C), RS1000969191 (19:16679297 G>A,T), RS1001054878 (19:16673505 T>C), RS1001243298 (19:16685189 C>T), RS1001345114 (19:16679808 T>C), RS1001351526 (19:16667291 G>A)

Disease associations

OMIM: gene MIM:611235 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

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
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression, affects cotreatment	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
clothianidin	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Aldehydes	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Lead	affects expression	1
Methyl Methanesulfonate	decreases expression	1
Silicon Dioxide	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Vincristine	decreases expression	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1
S-Nitrosoglutathione	increases expression	1

Clinical trials (associated diseases)

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