TMCC2

Summary

TMCC2 (transmembrane and coiled-coil domain family 2, HGNC:24239) is a protein-coding gene on chromosome 1q32.1, encoding Transmembrane and coiled-coil domains protein 2 (O75069). May be involved in the regulation of the proteolytic processing of the amyloid precursor protein (APP) possibly also implicating APOE.

Involved in amyloid precursor protein metabolic process. Located in endoplasmic reticulum.

Source: NCBI Gene 9911 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_014858

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24239
Approved symbol	TMCC2
Name	transmembrane and coiled-coil domain family 2
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	HUCEP11, FLJ38497
Ensembl gene	ENSG00000133069
Ensembl biotype	protein_coding
OMIM	619429
Entrez	9911

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000329800, ENST00000330675, ENST00000358024, ENST00000367159, ENST00000468846, ENST00000481950, ENST00000495538, ENST00000545499, ENST00000637895, ENST00000648708, ENST00000907462, ENST00000962349

RefSeq mRNA: 7 — MANE Select: NM_014858 NM_001242925, NM_001297611, NM_001297613, NM_001331034, NM_001375651, NM_001375652, NM_014858

CCDS: CCDS30984, CCDS55676, CCDS73010, CCDS76257, CCDS81418

Canonical transcript exons

ENST00000358024 — 5 exons

Exon	Start	End
ENSE00001443661	205227946	205228771
ENSE00003569246	205271813	205273343
ENSE00003595759	205241505	205242044
ENSE00003596480	205271120	205271255
ENSE00003606912	205268950	205269884

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3973 / max 4159.7688, expressed in 1394 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8018	9.7395	1338
8024	4.7126	68
8021	1.0600	200
8019	0.3017	140
8026	0.2847	16
8027	0.0806	22
8028	0.0742	40
8020	0.0727	49
8022	0.0385	20
201897	0.0208	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	96.23	gold quality
spinal cord	UBERON:0002240	95.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.26	gold quality
cerebellar hemisphere	UBERON:0002245	95.12	gold quality
cerebellar cortex	UBERON:0002129	95.05	gold quality
inferior vagus X ganglion	UBERON:0005363	94.40	gold quality
amygdala	UBERON:0001876	94.39	gold quality
cerebellum	UBERON:0002037	94.12	gold quality
right frontal lobe	UBERON:0002810	94.00	gold quality
prefrontal cortex	UBERON:0000451	93.18	gold quality
cingulate cortex	UBERON:0003027	93.11	gold quality
anterior cingulate cortex	UBERON:0009835	93.01	gold quality
Ammon’s horn	UBERON:0001954	92.98	gold quality
midbrain	UBERON:0001891	92.79	gold quality
substantia nigra	UBERON:0002038	92.79	gold quality
putamen	UBERON:0001874	92.76	gold quality
trabecular bone tissue	UBERON:0002483	92.74	gold quality
hypothalamus	UBERON:0001898	92.71	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.59	gold quality
nucleus accumbens	UBERON:0001882	92.00	gold quality
ventral tegmental area	UBERON:0002691	91.87	gold quality
pons	UBERON:0000988	91.53	gold quality
subthalamic nucleus	UBERON:0001906	91.51	gold quality
frontal cortex	UBERON:0001870	91.48	gold quality
neocortex	UBERON:0001950	91.35	gold quality
cortical plate	UBERON:0005343	91.30	gold quality
telencephalon	UBERON:0001893	91.14	gold quality
caudate nucleus	UBERON:0001873	91.09	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.03	gold quality
central nervous system	UBERON:0001017	90.88	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	1158.88
E-CURD-98	yes	648.32
E-MTAB-9221	yes	11.27
E-HCAD-9	yes	6.65
E-MTAB-9067	yes	5.25
E-CURD-112	no	2.10
E-HCAD-10	no	1.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting TMCC2, 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-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-7106-5P	99.53	67.47	3574

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmcc2	ENSDARG00000046007
mus_musculus	Tmcc2	ENSMUSG00000042066
rattus_norvegicus	Tmcc2	ENSRNOG00000000033
drosophila_melanogaster	Dmtn	FBGN0037443
caenorhabditis_elegans		WBGENE00015800

Paralogs (3): TMCC3 (ENSG00000057704), TMCC1 (ENSG00000172765), TEX28 (ENSG00000278057)

Protein

Protein identifiers

Transmembrane and coiled-coil domains protein 2 — O75069 (reviewed: O75069)

Alternative names: Cerebral protein 11

All UniProt accessions (2): A0A0C4DFR1, O75069

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the regulation of the proteolytic processing of the amyloid precursor protein (APP) possibly also implicating APOE.

Subunit / interactions. May form homodimers and heterodimers with TMCC2 or TMCC3 via the coiled-coil domains. Interacts with ribosomal proteins RPL4 and RPS6. Interacts with APOE and proteolytic processed C-terminal fragment C99 of the amyloid precursor protein (APP C99).

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the TEX28 family.

Isoforms (4)

UniProt ID	Names	Canonical?
O75069-1	1	yes
O75069-2	2
O75069-3	3
O75069-5	5

RefSeq proteins (7): NP_001229854, NP_001284540, NP_001284542, NP_001317963, NP_001362580, NP_001362581, NP_055673* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019394	TEX28/TMCC	Family

Pfam: PF10267

UniProt features (26 total): compositionally biased region 6, modified residue 6, splice variant 3, sequence conflict 3, region of interest 3, transmembrane region 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75069-F1	61.98	0.26

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 (6): 6, 163, 438, 464, 470, 503

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 168 (showing top): MODULE_255, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MODULE_317, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GNF2_ANK1, MODULE_66, MARTINEZ_RB1_TARGETS_DN, GNF2_SPTA1, HNF1_C, GOBP_AMYLOID_PRECURSOR_PROTEIN_METABOLIC_PROCESS, CUI_TCF21_TARGETS_2_DN, VANTVEER_BREAST_CANCER_ESR1_DN, PIT1_Q6, MODULE_11

GO Biological Process (1): amyloid precursor protein metabolic process (GO:0042982)

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

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

664 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMCC2	APP	P05067	717
TMCC2	APOE	P02649	489
TMCC2	DSTYK	Q6XUX3	472
TMCC2	CORO1A	P31146	444
TMCC2	TSPO2	Q5TGU0	407
TMCC2	TMEM81	Q6P7N7	398
TMCC2	OR5M11	Q96RB7	386
TMCC2	ZNF101	Q8IZC7	383
TMCC2	GYPB	P06028	366
TMCC2	FAM241B	Q96D05	356
TMCC2	TEX26	Q8N6G2	354
TMCC2	OR51B2	Q9Y5P1	353
TMCC2	RUNDC3A	Q59EK9	337
TMCC2	FAM178B	Q8IXR5	330
TMCC2	GYPE	P15421	321

IntAct

29 interactions, top by confidence:

A	B	Type	Score
TEX28	TMCC2	psi-mi:“MI:0914”(association)	0.640
APOE	TMCC2	psi-mi:“MI:0915”(physical association)	0.590
TMCC2	APOE	psi-mi:“MI:0915”(physical association)	0.590
TMCC2	APOE	psi-mi:“MI:0407”(direct interaction)	0.590
TMCC2	TMCC2	psi-mi:“MI:0915”(physical association)	0.560
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
TMCC2	CORO1A	psi-mi:“MI:0914”(association)	0.530
APP	TMCC2	psi-mi:“MI:0915”(physical association)	0.400
TMCC2	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
TMCC2	SMO	psi-mi:“MI:0915”(physical association)	0.370
TMCC2	IQUB	psi-mi:“MI:0915”(physical association)	0.370
TMCC2	ZNF581	psi-mi:“MI:0915”(physical association)	0.370
TEX28	NBAS	psi-mi:“MI:0914”(association)	0.350
TMCC2	MARK3	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
TMCC2	RPS4Y1	psi-mi:“MI:0914”(association)	0.350
TEX28	PRAF2	psi-mi:“MI:0914”(association)	0.350
TMCC1	TMCC2	psi-mi:“MI:0914”(association)	0.350
PTOV1	TMCC2	psi-mi:“MI:0915”(physical association)	0.000
UBA1	TMCC2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (59): TMCC2 (Two-hybrid), TMCC2 (Two-hybrid), TMCC2 (Two-hybrid), TMCC2 (Two-hybrid), TMCC2 (Two-hybrid), KAT5 (Two-hybrid), DIP2A (Two-hybrid), PRPF31 (Two-hybrid), WT1-AS (Two-hybrid), AMOTL2 (Two-hybrid), ZNF581 (Two-hybrid), FAM90A1 (Two-hybrid), ZNF250 (Two-hybrid), CCDC33 (Two-hybrid), FAM161A (Two-hybrid)

ESM2 similar proteins: A0JMF8, A2RSY1, A6QLW9, B1WAV2, B2GV50, O60271, O75069, O77627, P05412, P05627, P0C090, P17325, P22670, P48377, P48378, P48379, P48380, P48381, P56432, Q0V989, Q0V9K5, Q16656, Q32NR3, Q3KR73, Q499B3, Q49GP3, Q4R3I8, Q4R3Z4, Q4V872, Q4VGL6, Q58A65, Q5EAP5, Q5EY87, Q5RDR2, Q5RJA1, Q5TC82, Q62739, Q66IV1, Q6NRE7, Q6NUC6

Diamond homologs: O75069, O94876, Q69ZZ6, Q80W04, Q8R310, Q9ULS5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	2
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1161 predictions. Top by Δscore:

Variant	Effect	Δscore
1:205269883:AGG:A	donor_loss	1.0000
1:205269885:G:A	donor_loss	1.0000
1:205269885:G:GG	donor_gain	1.0000
1:205271114:C:A	acceptor_gain	1.0000
1:205271119:GGT:G	acceptor_gain	1.0000
1:205271252:CCAG:C	donor_loss	1.0000
1:205271253:CAG:C	donor_loss	1.0000
1:205271255:GG:G	donor_loss	1.0000
1:205271807:CTGCA:C	acceptor_loss	1.0000
1:205271808:TGCA:T	acceptor_loss	1.0000
1:205271809:GCAG:G	acceptor_loss	1.0000
1:205271810:CAG:C	acceptor_loss	1.0000
1:205271811:AGG:A	acceptor_loss	1.0000
1:205271812:G:GC	acceptor_loss	1.0000
1:205228767:TAAAG:T	donor_loss	0.9900
1:205228768:AAAGG:A	donor_loss	0.9900
1:205228769:AAGG:A	donor_loss	0.9900
1:205228771:GGT:G	donor_loss	0.9900
1:205228772:GTGA:G	donor_loss	0.9900
1:205228773:T:A	donor_loss	0.9900
1:205241503:A:G	acceptor_gain	0.9900
1:205242040:ACAAG:A	donor_loss	0.9900
1:205242041:CAAGG:C	donor_loss	0.9900
1:205242042:AAGG:A	donor_loss	0.9900
1:205242043:AGG:A	donor_loss	0.9900
1:205242044:GGTGA:G	donor_loss	0.9900
1:205242045:GT:G	donor_loss	0.9900
1:205242046:T:G	donor_loss	0.9900
1:205268947:CAG:C	acceptor_loss	0.9900
1:205268948:AGGTC:A	acceptor_gain	0.9900

AlphaMissense

4626 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:205269077:T:C	L292P	1.000
1:205269151:T:C	Y317H	1.000
1:205269151:T:G	Y317D	1.000
1:205269152:A:C	Y317S	1.000
1:205269152:A:G	Y317C	1.000
1:205269155:T:C	L318P	1.000
1:205269161:T:C	L320P	1.000
1:205269201:G:C	K333N	1.000
1:205269201:G:T	K333N	1.000
1:205269208:T:C	F336L	1.000
1:205269209:T:C	F336S	1.000
1:205269209:T:G	F336C	1.000
1:205269210:C:A	F336L	1.000
1:205269210:C:G	F336L	1.000
1:205269220:A:G	N340D	1.000
1:205269251:T:C	L350P	1.000
1:205269263:T:C	L354P	1.000
1:205269497:T:A	I432N	1.000
1:205269866:T:C	L555P	1.000
1:205269878:G:C	R559P	1.000
1:205271128:G:C	R564P	1.000
1:205271131:T:C	L565P	1.000
1:205271140:A:C	Q568P	1.000
1:205271143:T:C	L569P	1.000
1:205271152:T:C	L572P	1.000
1:205271161:T:C	L575P	1.000
1:205271163:C:G	H576D	1.000
1:205271167:A:C	Q577P	1.000
1:205271185:T:C	L583P	1.000
1:205271197:T:C	L587P	1.000

dbSNP variants (sampled 300 via entrez): RS1000010210 (1:205273346 C>T), RS1000093790 (1:205231540 T>A), RS1000282860 (1:205262402 G>A), RS1000358808 (1:205255270 C>T), RS1000366659 (1:205249529 CT>C), RS1000392189 (1:205243191 C>G), RS1000440140 (1:205249710 C>G), RS1000446408 (1:205230745 TGG>T), RS1000535081 (1:205249965 G>A,C), RS1000619598 (1:205256461 C>T), RS1000702874 (1:205248330 G>A), RS1000775067 (1:205264069 T>C), RS1000827480 (1:205248479 C>T), RS1000949657 (1:205250287 T>C), RS1001012956 (1:205260978 C>G,T)

Disease associations

OMIM: gene MIM:619429 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST000497_7	Mean platelet volume	1.000000e-20
GCST001335_7	Mean platelet volume	4.000000e-27
GCST001337_3	Platelet count	3.000000e-14
GCST002184_3	Mean platelet volume	3.000000e-13
GCST004599_262	Mean platelet volume	7.000000e-76
GCST004599_263	Mean platelet volume	1.000000e-210
GCST004602_24	Mean corpuscular volume	4.000000e-20
GCST004605_75	Mean corpuscular hemoglobin concentration	2.000000e-20
GCST004611_1	High light scatter reticulocyte count	1.000000e-23
GCST004612_158	High light scatter reticulocyte percentage of red cells	4.000000e-20
GCST004616_122	Platelet distribution width	4.000000e-11
GCST004619_214	Reticulocyte fraction of red cells	4.000000e-10
GCST004628_136	Immature fraction of reticulocytes	5.000000e-27
GCST004630_18	Mean corpuscular hemoglobin	2.000000e-33
GCST005993_65	Mean corpuscular hemoglobin	1.000000e-10
GCST010143_34	Meat-related diet	1.000000e-08
GCST010143_9	Meat-related diet	4.000000e-11
GCST010697_12	Cortical surface area (min-P)	6.000000e-10
GCST010698_16	Subcortical volume (min-P)	8.000000e-09
GCST010699_52	Brain morphology (min-P)	5.000000e-08
GCST010700_66	Cortical thickness (MOSTest)	3.000000e-09
GCST010701_17	Cortical surface area (MOSTest)	5.000000e-08
GCST010702_2	Subcortical volume (MOSTest)	3.000000e-08
GCST010703_27	Brain morphology (MOSTest)	5.000000e-09
GCST90002380_120	Basophil percentage of white cells	6.000000e-10
GCST90002385_103	High light scatter reticulocyte count	3.000000e-58
GCST90002386_389	High light scatter reticulocyte percentage of red cells	2.000000e-47
GCST90002387_241	Immature fraction of reticulocytes	8.000000e-44
GCST90002387_242	Immature fraction of reticulocytes	2.000000e-16
GCST90002390_334	Mean corpuscular hemoglobin	1.000000e-37

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007986	reticulocyte count
EFO:0007984	platelet component distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007992	basophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004833	neutrophil count
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
HC toxin	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, decreases reaction	1
15-acetyldeoxynivalenol	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
oxamflatin	increases expression	1
apicidin	increases expression	1
scriptaid	increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Panobinostat	increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Caffeine	increases expression	1
Cisplatin	increases expression	1

Clinical trials (associated diseases)

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