TLCD2

Summary

TLCD2 (TLC domain containing 2, HGNC:33522) is a protein-coding gene on chromosome 17p13.3, encoding TLC domain-containing protein 2 (A6NGC4). Regulates the composition and fluidity of the plasma membrane.

Involved in several processes, including membrane assembly; phospholipid homeostasis; and regulation of membrane lipid distribution. Located in plasma membrane.

Source: NCBI Gene 727910 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_001164407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33522
Approved symbol	TLCD2
Name	TLC domain containing 2
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000185561
Ensembl biotype	protein_coding
OMIM	620967
Entrez	727910

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000330676

RefSeq mRNA: 1 — MANE Select: NM_001164407 NM_001164407

CCDS: CCDS45567

Canonical transcript exons

ENST00000330676 — 4 exons

Exon	Start	End
ENSE00001299632	1709499	1709581
ENSE00001326501	1702816	1708222
ENSE00001328339	1709804	1709886
ENSE00001390861	1710067	1710377

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 83.48.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2665 / max 47.9509, expressed in 680 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163773	0.6690	341
163774	0.5523	297
163775	0.0452	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	83.48	gold quality
colonic epithelium	UBERON:0000397	80.45	gold quality
left adrenal gland	UBERON:0001234	79.72	gold quality
right adrenal gland	UBERON:0001233	79.70	gold quality
left adrenal gland cortex	UBERON:0035825	79.65	gold quality
right adrenal gland cortex	UBERON:0035827	78.65	gold quality
adrenal gland	UBERON:0002369	78.57	gold quality
duodenum	UBERON:0002114	78.54	gold quality
transverse colon	UBERON:0001157	77.22	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.61	gold quality
stromal cell of endometrium	CL:0002255	76.08	gold quality
adipose tissue	UBERON:0001013	75.57	gold quality
rectum	UBERON:0001052	75.06	gold quality
calcaneal tendon	UBERON:0003701	74.44	gold quality
small intestine	UBERON:0002108	74.05	gold quality
omental fat pad	UBERON:0010414	73.95	gold quality
mucosa of stomach	UBERON:0001199	73.69	gold quality
colon	UBERON:0001155	73.68	gold quality
sural nerve	UBERON:0015488	73.62	gold quality
intestine	UBERON:0000160	73.53	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.51	gold quality
esophagus mucosa	UBERON:0002469	72.67	gold quality
esophagus	UBERON:0001043	71.40	gold quality
right lung	UBERON:0002167	70.94	gold quality
lung	UBERON:0002048	70.75	gold quality
upper lobe of left lung	UBERON:0008952	70.74	gold quality
tibial nerve	UBERON:0001323	70.52	gold quality
liver	UBERON:0002107	70.50	gold quality
thoracic mammary gland	UBERON:0005200	70.01	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

155 targeting TLCD2, 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-5193	100.00	67.26	1744
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6817-3P	99.79	68.35	2126

Literature-anchored findings (GeneRIF, showing 2)

• inhibition of FLD-1 or TLCD1/2 prevents lipotoxicity by allowing increased levels of membrane phospholipids that contain fluidizing long-chain polyunsaturated fatty acids. (PMID:30509349)
• TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis. (PMID:36241646)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tlcd2	ENSDARG00000077396
mus_musculus	Tlcd2	ENSMUSG00000038217
rattus_norvegicus	Tlcd2	ENSRNOG00000037275
caenorhabditis_elegans	fld-1	WBGENE00013407
caenorhabditis_elegans		WBGENE00019686
caenorhabditis_elegans	Y48G8AL.13	WBGENE00021691

Paralogs (5): TLCD3B (ENSG00000149926), TLCD4 (ENSG00000152078), TLCD1 (ENSG00000160606), TLCD3A (ENSG00000167695), CLN8 (ENSG00000182372)

Protein

Protein identifiers

TLC domain-containing protein 2 — A6NGC4 (reviewed: A6NGC4)

All UniProt accessions (1): A6NGC4

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the composition and fluidity of the plasma membrane. Inhibits the incorporation of membrane-fluidizing phospholipids containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA) and thereby promotes membrane rigidity. Does not appear to have any effect on LCPUFA synthesis.

Subcellular location. Cell membrane.

Similarity. Belongs to the TLCD family.

RefSeq proteins (1): NP_001157879* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006634	TLC-dom	Domain
IPR050846	TLCD	Family

Pfam: PF03798

UniProt features (11 total): transmembrane region 6, compositionally biased region 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NGC4-F1	86.34	0.69

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 89 (showing top): GOBP_MEMBRANE_BIOGENESIS, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_LIPID_HOMEOSTASIS, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MEMBRANE_ORGANIZATION, GOBP_HOMEOSTATIC_PROCESS, MARSON_BOUND_BY_FOXP3_STIMULATED, GOBP_CHEMICAL_HOMEOSTASIS, WANG_SMARCE1_TARGETS_UP, DODD_NASOPHARYNGEAL_CARCINOMA_DN, OHGUCHI_LIVER_HNF4A_TARGETS_DN, GOBP_PHOSPHOLIPID_HOMEOSTASIS, CBX7_TARGET_GENES

GO Biological Process (4): plasma membrane organization (GO:0007009), phospholipid homeostasis (GO:0055091), membrane assembly (GO:0071709), regulation of membrane lipid distribution (GO:0097035)

GO Molecular Function (0):

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane organization	3
endomembrane system organization	1
lipid homeostasis	1
cellular component assembly	1
membrane biogenesis	1
regulation of biological quality	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLCD2	WDR81	Q562E7	502
TLCD2	CCDC125	Q86Z20	415
TLCD2	TXNDC15	Q96J42	390
TLCD2	GATD1	Q8NB37	379
TLCD2	CMC4	P56277	370
TLCD2	BHLHA9	Q7RTU4	366
TLCD2	OVCA2	Q8WZ82	358
TLCD2	ADIPOR2	Q86V24	357
TLCD2	MED15	Q96RN5	354
TLCD2	ZNF337	Q9Y3M9	350
TLCD2	TLCD3A	Q8TBR7	338
TLCD2	SYAP1	Q96A49	338
TLCD2	CLN8	Q9UBY8	324
TLCD2	TMEM154	Q6P9G4	311
TLCD2	BOLA1	Q9Y3E2	297

IntAct

12 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SLC9A6	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TMEM30A	TLCD2	psi-mi:“MI:0914”(association)	0.350
SLC6A20	TLCD2	psi-mi:“MI:0914”(association)	0.350
GPR12	TLCD2	psi-mi:“MI:0914”(association)	0.350
TSPAN1	TLCD2	psi-mi:“MI:0914”(association)	0.350
SLC6A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
TCTN3	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270
TCTN2	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (12): TLCD2 (Affinity Capture-MS), TLCD2 (Proximity Label-MS), TLCD2 (Proximity Label-MS), TLCD2 (Proximity Label-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS), TLCD2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4P6, A1A5B4, A5PK40, A6NDV4, A6NFX1, A6NGC4, A6QL84, A6QLK4, B1AWJ5, B6ID01, E1BY51, P58749, Q2TA01, Q2YDG0, Q32PG7, Q3T9M1, Q4R7X9, Q5HZE5, Q5JZQ7, Q5R6H1, Q5RBY7, Q60HE8, Q6AY05, Q6AYM9, Q6PHN7, Q6TCG5, Q6UX01, Q6UXD7, Q7RTT9, Q7Z403, Q80ZE4, Q8CE47, Q8R139, Q8TBR7, Q96FZ5, Q96HE8, Q96S97, Q9BSA9, Q9BZW5, Q9CQC4

Diamond homologs: A6NGC4, A8WGS4, F1NZP5, G5EF48, Q8VC26, Q96CP7, Q5U2T1, Q99JT6, Q6GLX2, Q6P4N1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

544 predictions. Top by Δscore:

Variant	Effect	Δscore
17:1709468:T:TA	donor_gain	0.9900
17:1709493:TCTCA:T	donor_loss	0.9900
17:1709495:TCA:T	donor_loss	0.9900
17:1709497:A:AT	donor_loss	0.9900
17:1709498:C:CG	donor_loss	0.9900
17:1709498:CCA:C	donor_gain	0.9900
17:1709532:G:A	donor_gain	0.9900
17:1709580:ACCT:A	acceptor_loss	0.9900
17:1709582:C:CC	acceptor_gain	0.9900
17:1709802:A:T	donor_loss	0.9900
17:1709802:AC:A	donor_gain	0.9900
17:1709803:C:CG	donor_loss	0.9900
17:1709803:CC:C	donor_gain	0.9900
17:1709803:CCCA:C	donor_gain	0.9900
17:1710123:C:CT	donor_gain	0.9900
17:1710124:C:CT	donor_gain	0.9900
17:1708012:TCATC:T	donor_gain	0.9800
17:1708013:CATCC:C	donor_gain	0.9800
17:1708014:ATCCA:A	donor_gain	0.9800
17:1709578:TAAC:T	acceptor_gain	0.9800
17:1709790:C:A	donor_gain	0.9800
17:1709802:A:AC	donor_gain	0.9800
17:1709803:C:CC	donor_gain	0.9800
17:1710126:C:CT	donor_gain	0.9800
17:1710350:C:A	donor_gain	0.9800
17:1707765:T:TA	donor_gain	0.9700
17:1708120:T:TA	donor_gain	0.9700
17:1708221:ACCTG:A	acceptor_loss	0.9700
17:1708222:CCTGG:C	acceptor_loss	0.9700
17:1708223:C:A	acceptor_loss	0.9700

AlphaMissense

1668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1707923:G:C	S214R	0.972
17:1707923:G:T	S214R	0.972
17:1707925:T:G	S214R	0.972
17:1709574:G:C	F89L	0.968
17:1709574:G:T	F89L	0.968
17:1709576:A:G	F89L	0.968
17:1708205:G:C	S120R	0.950
17:1708205:G:T	S120R	0.950
17:1708207:T:G	S120R	0.950
17:1708214:G:C	S117R	0.947
17:1708214:G:T	S117R	0.947
17:1708216:T:G	S117R	0.947
17:1708079:G:C	F162L	0.944
17:1708079:G:T	F162L	0.944
17:1708081:A:G	F162L	0.944
17:1710096:G:C	S49R	0.944
17:1710096:G:T	S49R	0.944
17:1710098:T:G	S49R	0.944
17:1710195:G:C	F16L	0.942
17:1710195:G:T	F16L	0.942
17:1710197:A:G	F16L	0.942
17:1708142:G:C	N141K	0.941
17:1708142:G:T	N141K	0.941
17:1709510:G:C	H111D	0.937
17:1708010:A:C	S185R	0.933
17:1708010:A:T	S185R	0.933
17:1708012:T:G	S185R	0.933
17:1709804:C:G	G87R	0.918
17:1708143:T:A	N141I	0.916
17:1709579:A:G	Y88H	0.914

dbSNP variants (sampled 300 via entrez): RS1000072368 (17:1710432 G>A,C), RS1000073451 (17:1709560 G>C), RS1000315653 (17:1705605 C>G,T), RS1000659602 (17:1712140 AT>A,ATT), RS1000813418 (17:1707294 T>C), RS1001523305 (17:1709443 G>A,T), RS1001588325 (17:1704146 G>A), RS1001742613 (17:1709164 G>A), RS1001884999 (17:1703000 G>A), RS1001899470 (17:1707810 G>A,T), RS1001930738 (17:1707614 A>G), RS1001937239 (17:1702724 A>T), RS1002097562 (17:1708229 G>A), RS1002497075 (17:1708362 C>A,G), RS1002517069 (17:1703933 AT>A,ATT)

Disease associations

OMIM: gene MIM:620967 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90011900_146	Serum alkaline phosphatase levels	2.000000e-33

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
entinostat	increases expression	1
monomethylarsonous acid	decreases expression	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
jinfukang	increases expression	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, increases expression	1
Copper	affects binding, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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