MTCL3

Summary

MTCL3 (MTCL family member 3, HGNC:21494) is a protein-coding gene on chromosome 6q22.33, encoding Microtubule cross-linking factor 3 (Q5TF21).

Predicted to be involved in regulation of autophagy. Predicted to be located in extracellular space and membrane.

Source: NCBI Gene 387104 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 116 total
• Druggable target: yes
• MANE Select transcript: NM_001400265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21494
Approved symbol	MTCL3
Name	MTCL family member 3
Location	6q22.33
Locus type	gene with protein product
Status	Approved
Aliases	dJ403A15.3
Ensembl gene	ENSG00000214338
Ensembl biotype	protein_coding
Entrez	387104

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000465909, ENST00000467753, ENST00000525778, ENST00000703793

RefSeq mRNA: 1 — MANE Select: NM_001400265 NM_001400265

CCDS: CCDS43505

Canonical transcript exons

ENST00000525778 — 7 exons

Exon	Start	End
ENSE00002176844	127472974	127473391
ENSE00002197544	127518579	127519335
ENSE00003475182	127475293	127476468
ENSE00003496743	127514823	127515047
ENSE00003609368	127515514	127516702
ENSE00003645137	127482913	127482984
ENSE00003671372	127512891	127513049

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 83.64.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6100 / max 422.8477, expressed in 760 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75435	1.7832	415
75447	1.4707	291
75444	1.1593	278
75441	0.4188	211
75442	0.3006	137
75446	0.1216	50
75443	0.1059	56
75440	0.0941	38
75434	0.0817	21
75448	0.0523	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	83.64	gold quality
cortical plate	UBERON:0005343	83.31	gold quality
ventricular zone	UBERON:0003053	79.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.43	gold quality
sural nerve	UBERON:0015488	76.86	gold quality
prefrontal cortex	UBERON:0000451	75.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.97	silver quality
corpus callosum	UBERON:0002336	72.91	gold quality
islet of Langerhans	UBERON:0000006	68.95	gold quality
stromal cell of endometrium	CL:0002255	67.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.33	gold quality
frontal cortex	UBERON:0001870	64.11	gold quality
calcaneal tendon	UBERON:0003701	59.27	gold quality
placenta	UBERON:0001987	58.96	gold quality
urinary bladder	UBERON:0001255	58.86	gold quality
endometrium	UBERON:0001295	58.80	gold quality
smooth muscle tissue	UBERON:0001135	58.44	gold quality
adrenal tissue	UBERON:0018303	58.17	gold quality
right lung	UBERON:0002167	57.88	gold quality
mucosa of stomach	UBERON:0001199	57.42	gold quality
vermiform appendix	UBERON:0001154	56.90	gold quality
adenohypophysis	UBERON:0002196	56.55	gold quality
pituitary gland	UBERON:0000007	56.34	gold quality
gall bladder	UBERON:0002110	55.67	gold quality
bone marrow cell	CL:0002092	55.39	gold quality
cerebral cortex	UBERON:0000956	55.33	gold quality
lung	UBERON:0002048	54.71	gold quality
substantia nigra	UBERON:0002038	54.50	gold quality
rectum	UBERON:0001052	54.41	gold quality
fallopian tube	UBERON:0003889	54.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

348 targeting MTCL3, 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-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtcl3a	ENSDARG00000063311
danio_rerio	mtcl3b	ENSDARG00000075455
mus_musculus	Mtcl3	ENSMUSG00000038916
rattus_norvegicus	Mtcl3	ENSRNOG00000012324

Paralogs (2): MTCL2 (ENSG00000149639), MTCL1 (ENSG00000168502)

Protein

Protein identifiers

Microtubule cross-linking factor 3 — Q5TF21 (reviewed: Q5TF21)

All UniProt accessions (4): A0A1D5RMT3, A0A994J4H7, E9PJP2, Q5TF21

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Similarity. Belongs to the MTCL family.

RefSeq proteins (1): NP_001387194* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027881	SOGA_CC	Domain
IPR049885	MTCL1-3	Family

Pfam: PF11365

UniProt features (23 total): compositionally biased region 12, region of interest 4, modified residue 2, coiled-coil region 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TF21-F1	66.58	0.31

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 (2): 569, 781

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 79 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, GOBP_REGULATION_OF_CATABOLIC_PROCESS, chr6q22, CHENG_IMPRINTED_BY_ESTRADIOL, MIKKELSEN_MEF_ICP_WITH_H3K27ME3, MIKKELSEN_ES_ICP_WITH_H3K4ME3, MIKKELSEN_NPC_ICP_WITH_H3K4ME3, GOBP_PROCESS_UTILIZING_AUTOPHAGIC_MECHANISM, RAO_BOUND_BY_SALL4_ISOFORM_B, ZSCAN21_TARGET_GENES, ZSCAN5C_TARGET_GENES, MIR153_5P, MIR8485

GO Biological Process (1): regulation of autophagy (GO:0010506)

GO Molecular Function (0):

GO Cellular Component (2): obsolete extracellular space (GO:0005615), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
autophagy	1
regulation of catabolic process	1
cellular anatomical structure	1

Protein interactions and networks

STRING

280 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTCL3	C6orf58	Q6P5S2	638
MTCL3	KIAA0408	Q6ZU52	570
MTCL3	ECHDC1	Q9NTX5	441
MTCL3	CHCT1	Q86WR6	419
MTCL3	PCDHGB5	Q9Y5G0	416
MTCL3	RIPPLY2	Q5TAB7	408
MTCL3	A6NDT3	A6NDT3	403
MTCL3	RGPD1	P0C839	380
MTCL3	MAP10	Q9P2G4	374
MTCL3	NECAB1	Q8N987	370
MTCL3	BRINP1	O60477	365
MTCL3	ABI3	Q9P2A4	359
MTCL3	CARMIL3	Q8ND23	353
MTCL3	PTPRK	Q15262	353
MTCL3	RNF43	Q68DV7	353

IntAct

47 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	PPFIA3	psi-mi:“MI:0914”(association)	0.670
REEP5	SCAMP1	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
ZNF214	LRP4	psi-mi:“MI:0914”(association)	0.530
NRBF2	GALT	psi-mi:“MI:0914”(association)	0.530
PPP2R5A	AXIN1	psi-mi:“MI:0914”(association)	0.530
REEP5	PLSCR1	psi-mi:“MI:0914”(association)	0.530
PPP2R1A	ENSA	psi-mi:“MI:0914”(association)	0.530
TPST1	TPST2	psi-mi:“MI:0914”(association)	0.530
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
HS2ST1	USP9Y	psi-mi:“MI:0914”(association)	0.350
	ARID1A	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CDK5RAP2	SPTBN2	psi-mi:“MI:0914”(association)	0.350
CEP63	CIBAR1	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
CHD8	IGLV4-60	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	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
RTN4	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Proximity Label-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), EFHD1 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS)

ESM2 similar proteins: A2AHC3, A2AMT1, A6NCC3, A6NN73, D3Z8E6, D6RF30, E7F5E1, H3BPF8, H3BQL2, H3BSY2, O15061, O35668, P0DX52, P0DX53, P53814, P54256, P54257, P62025, P97434, Q02435, Q06002, Q06637, Q0D2H9, Q0VF96, Q12934, Q3UHU5, Q3V0F0, Q5DU05, Q5T5Y3, Q5TF21, Q60664, Q62627, Q63312, Q6AW69, Q6NZL0, Q6PHN1, Q6WCQ1, Q70IV5, Q80VC9, Q80Y56

Diamond homologs: E1U8D0, O94964, Q3UHU5, Q5TF21, Q6NZL0, Q9Y4B5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Amplification of signal from the kinetochores	5	24.6×	4e-05
Mitotic Spindle Checkpoint	5	19.8×	1e-04
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	5	14.6×	4e-04
Signaling by WNT	5	14.0×	4e-04
Mitotic Metaphase and Anaphase	5	12.1×	7e-04
Mitotic Anaphase	5	12.1×	7e-04
EML4 and NUDC in mitotic spindle formation	5	11.6×	8e-04
M Phase	7	11.6×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	106
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1547 predictions. Top by Δscore:

Variant	Effect	Δscore
6:127476474:T:C	acceptor_gain	1.0000
6:127476474:T:TC	acceptor_gain	1.0000
6:127482981:ATAAC:A	acceptor_loss	1.0000
6:127482982:TAA:T	acceptor_gain	1.0000
6:127482982:TAACT:T	acceptor_loss	1.0000
6:127482983:AAC:A	acceptor_loss	1.0000
6:127482984:AC:A	acceptor_loss	1.0000
6:127482985:C:CC	acceptor_gain	1.0000
6:127482985:C:T	acceptor_loss	1.0000
6:127482985:CTGAA:C	acceptor_loss	1.0000
6:127512887:TAACC:T	donor_loss	1.0000
6:127512888:AAC:A	donor_loss	1.0000
6:127512888:AACC:A	donor_loss	1.0000
6:127512889:A:AC	donor_gain	1.0000
6:127512889:A:AG	donor_loss	1.0000
6:127512889:ACCT:A	donor_gain	1.0000
6:127512890:C:CC	donor_gain	1.0000
6:127512890:C:CG	donor_loss	1.0000
6:127512890:C:CT	donor_loss	1.0000
6:127512890:CCT:C	donor_gain	1.0000
6:127512890:CCTC:C	donor_gain	1.0000
6:127513055:T:TC	acceptor_gain	1.0000
6:127513060:G:C	acceptor_gain	1.0000
6:127513060:G:GC	acceptor_gain	1.0000
6:127513064:T:C	acceptor_gain	1.0000
6:127513064:T:TC	acceptor_gain	1.0000
6:127514830:T:TA	donor_gain	1.0000
6:127515044:CGTT:C	acceptor_gain	1.0000
6:127515045:GTTCT:G	acceptor_loss	1.0000
6:127515046:TTC:T	acceptor_loss	1.0000

AlphaMissense

6176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:127473297:A:G	L943P	1.000
6:127473306:A:G	L940P	1.000
6:127473315:A:G	L937P	1.000
6:127473315:A:T	L937H	1.000
6:127473324:A:T	I934K	1.000
6:127473357:A:G	L923P	1.000
6:127473357:A:T	L923H	1.000
6:127473363:A:G	L921P	1.000
6:127473363:A:T	L921H	1.000
6:127473369:A:G	L919P	1.000
6:127475362:G:C	F888L	1.000
6:127475362:G:T	F888L	1.000
6:127475363:A:G	F888S	1.000
6:127475364:A:G	F888L	1.000
6:127475372:A:G	L885P	1.000
6:127475381:C:G	R882P	1.000
6:127475384:A:G	F881S	1.000
6:127475393:A:C	M878R	1.000
6:127475414:A:G	L871P	1.000
6:127475531:A:G	L832P	1.000
6:127475552:A:G	L825P	1.000
6:127475561:G:T	A822D	1.000
6:127475562:C:G	A822P	1.000
6:127475691:C:G	G779R	1.000
6:127475693:C:T	G778D	1.000
6:127475694:C:G	G778R	1.000
6:127475700:G:A	P776S	1.000
6:127475703:C:G	G775R	1.000
6:127475703:C:T	G775R	1.000
6:127475709:G:T	R773S	1.000

dbSNP variants (sampled 300 via entrez): RS1000070530 (6:127510347 T>C), RS1000086914 (6:127517650 T>C), RS1000110929 (6:127489895 G>C), RS1000115632 (6:127478797 T>C,G), RS1000122580 (6:127495551 G>A,C,T), RS1000229623 (6:127485948 G>A), RS1000380042 (6:127498629 G>A,C), RS1000491713 (6:127486097 T>G), RS1000549332 (6:127478420 C>G,T), RS1000606410 (6:127492400 A>T), RS1000657703 (6:127483952 A>C), RS1000721401 (6:127498965 A>G), RS1000819128 (6:127503874 T>C), RS1000966522 (6:127512502 A>G), RS1000987337 (6:127484355 TACAGG>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST003254_8	Urinary albumin-to-creatinine ratio in non-diabetics	3.000000e-06
GCST005956_74	Waist-to-hip ratio adjusted for BMI	2.000000e-15
GCST005957_4	Waist-to-hip ratio adjusted for BMI (age <50)	5.000000e-07
GCST005958_6	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-11
GCST005962_17	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-16
GCST006979_386	Heel bone mineral density	2.000000e-11
GCST007847_55	Type 2 diabetes	9.000000e-08
GCST009379_58	Type 2 diabetes	6.000000e-11
GCST009798_84	Asthma	3.000000e-10
GCST90020025_529	Waist-to-hip ratio adjusted for BMI	6.000000e-16
GCST90020026_810	Hip index	1.000000e-09
GCST90020027_1049	Waist-hip index	2.000000e-16
GCST90020029_1444	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007778	urinary albumin to creatinine ratio
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066436 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	Kd	5.265	nM	CHEMBL5653589
8.28	ED50	5.265	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149466: Binding affinity to human SOGA3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0053	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	5
methylmercuric chloride	increases expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Smoke	increases abundance, increases expression	1
Thimerosal	decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652508	Binding	Binding affinity to human SOGA3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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