TBC1D21

Summary

TBC1D21 (TBC1 domain family member 21, HGNC:28536) is a protein-coding gene on chromosome 15q24.1, encoding TBC1 domain family member 21 (Q8IYX1). Acts as a GTPase-activating protein for Rab family protein(s).

Enables GTPase activator activity and small GTPase binding activity. Predicted to be involved in plasma membrane to endosome transport; sperm axoneme assembly; and sperm mitochondrial sheath assembly. Located in extracellular exosome.

Source: NCBI Gene 161514 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_153356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28536
Approved symbol	TBC1D21
Name	TBC1 domain family member 21
Location	15q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC34741, MgcRabGAP
Ensembl gene	ENSG00000167139
Ensembl biotype	protein_coding
OMIM	620387
Entrez	161514

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000300504, ENST00000535547, ENST00000562056

RefSeq mRNA: 2 — MANE Select: NM_153356 NM_001286434, NM_153356

CCDS: CCDS10252, CCDS66822

Canonical transcript exons

ENST00000300504 — 11 exons

Exon	Start	End
ENSE00001110256	73886078	73886174
ENSE00001110257	73884151	73884245
ENSE00001110259	73885003	73885103
ENSE00001110264	73884781	73884891
ENSE00001163163	73887620	73887736
ENSE00001163169	73886512	73886612
ENSE00001277253	73888430	73888513
ENSE00001277293	73881644	73881747
ENSE00001277297	73881399	73881506
ENSE00001277308	73889069	73889214
ENSE00001277317	73873564	73873769

Expression profiles

Bgee: expression breadth broad, 29 present calls, max score 91.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0673 / max 66.7606, expressed in 3 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147616	0.0240	3
147619	0.0217	3
147617	0.0172	3
147618	0.0044	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	91.51	gold quality
left testis	UBERON:0004533	91.17	gold quality
testis	UBERON:0000473	88.08	gold quality
sperm	CL:0000019	82.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.10	gold quality
tibialis anterior	UBERON:0001385	71.74	silver quality
ileal mucosa	UBERON:0000331	66.34	silver quality
adult organism	UBERON:0007023	62.50	gold quality
pancreatic ductal cell	CL:0002079	62.24	silver quality
deltoid	UBERON:0001476	58.65	gold quality
myocardium	UBERON:0002349	55.39	gold quality
epithelial cell of pancreas	CL:0000083	54.92	gold quality
nasal cavity epithelium	UBERON:0005384	54.41	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
buccal mucosa cell	CL:0002336	53.38	gold quality
cerebellar vermis	UBERON:0004720	51.91	gold quality
upper leg skin	UBERON:0004262	51.76	silver quality
quadriceps femoris	UBERON:0001377	49.63	gold quality
skin of hip	UBERON:0001554	48.04	silver quality
vastus lateralis	UBERON:0001379	46.64	gold quality
middle temporal gyrus	UBERON:0002771	44.51	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
thymus	UBERON:0002370	43.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
oocyte	CL:0000023	43.08	gold quality
skeletal muscle tissue	UBERON:0001134	42.86	gold quality
gingival epithelium	UBERON:0001949	42.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting TBC1D21, 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-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-6747-3P	97.73	64.84	1596

Literature-anchored findings (GeneRIF, showing 3)

• MgcRabGAP is involved in acrosome/acroplaxome formation and cytoskeletal reorganization via Rab activity during mammalian spermiogenesis (PMID:21128978)
• Data indicate that single-nucleotide polymorphisms (SNPs) distributing in not only lysyl oxidase-like 1 gene (LOXL1) but also TBC1 domain family member 21 protein (TBC1D21) and promyelocytic leukemia protein (PML). (PMID:24938310)
• Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice. (PMID:32976492)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tbc1d21	ENSMUSG00000036244
rattus_norvegicus	Tbc1d21	ENSRNOG00000008737

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), TBC1D1 (ENSG00000065882), EVI5 (ENSG00000067208), TBC1D25 (ENSG00000068354), TBC1D2 (ENSG00000095383), TBC1D10A (ENSG00000099992), SGSM3 (ENSG00000100359), TBC1D17 (ENSG00000104946), TBC1D13 (ENSG00000107021), TBC1D12 (ENSG00000108239), TBC1D9 (ENSG00000109436), TBC1D30 (ENSG00000111490), TBC1D15 (ENSG00000121749), TBC1D5 (ENSG00000131374), TBC1D14 (ENSG00000132405), TBC1D8B (ENSG00000133138), TBC1D4 (ENSG00000136111), GRTP1 (ENSG00000139835), SGSM2 (ENSG00000141258), EVI5L (ENSG00000142459), TBCK (ENSG00000145348), USP6NL (ENSG00000148429), RABGAP1L (ENSG00000152061), SGSM1 (ENSG00000167037), TBC1D2B (ENSG00000167202), TBC1D16 (ENSG00000167291), TBC1D10B (ENSG00000169221), TBC1D10C (ENSG00000175463), TBC1D28 (ENSG00000189375), TBC1D9B (ENSG00000197226), TBC1D8 (ENSG00000204634), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512), TBC1D3 (ENSG00000274611)

Protein

Protein identifiers

TBC1 domain family member 21 — Q8IYX1 (reviewed: Q8IYX1)

Alternative names: Male germ cell Rab GTPase-activating protein

All UniProt accessions (2): Q8IYX1, H3BTA9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a GTPase-activating protein for Rab family protein(s). Essential for the establishment of male fertility, and is required for both the production of normal sperm number and sperm function. Plays an important role in the formation of intact mitochondria, outer dense fibers and axoneme within the sperm tail. Essential for sperm mitochondrial sheath formation and for the interactions of ARMC12 with VDAC2 and VDAC3. May be involved in acrosome formation and cytoskeletal reorganization during spermiogenesis, possibly by regulating RAB3A activity.

Subunit / interactions. Interacts with ACTB. Interacts with ARMC12, TOMM20, DNAH7 and RAP1A. Interacts with RAB10.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in round and elongated spermatids (at protein level). Expressed specifically in adult testis and very weakly in fetal brain.

Domain organisation. The arginine and glutamine fingers are critical for the GTPase-activating mechanism, they pull out Rab’s ‘switch 2’ glutamine and insert in Rab’s active site.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IYX1-1	1	yes
Q8IYX1-2	2

RefSeq proteins (2): NP_001273363, NP_699187* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily

Pfam: PF00566

UniProt features (6 total): site 2, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYX1-F1	93.19	0.84

Functional residue map

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

Catalytic / active sites (2): 124 (arginine finger); 163 (glutamine finger)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 77 (showing top): GOCC_SECRETORY_GRANULE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOMF_ACTIN_BINDING, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_REGULATION_OF_CILIUM_ASSEMBLY

GO Biological Process (6): spermatogenesis (GO:0007283), sperm axoneme assembly (GO:0007288), flagellated sperm motility (GO:0030317), plasma membrane to endosome transport (GO:0048227), sperm mitochondrial sheath assembly (GO:0120317), cell differentiation (GO:0030154)

GO Molecular Function (4): actin binding (GO:0003779), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (6): acrosomal vesicle (GO:0001669), cytoskeleton (GO:0005856), cytoplasmic vesicle (GO:0031410), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	2
sperm flagellum assembly	2
cellular anatomical structure	2
male gamete generation	1
axoneme assembly	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
vesicle-mediated transport	1
cellular component assembly	1
cellular developmental process	1
cytoskeletal protein binding	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
GTPase binding	1
binding	1
secretory granule	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular vesicle	1
extracellular vesicle	1
sperm flagellum	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBC1D21	TBC1D19	Q8N5T2	665
TBC1D21	TBC1D22B	Q9NU19	646
TBC1D21	TBC1D13	Q9NVG8	626
TBC1D21	ARMC12	Q5T9G4	611
TBC1D21	TBC1D20	Q96BZ9	594
TBC1D21	TBC1D10C	Q8IV04	589
TBC1D21	TBC1D1	Q86TI0	566
TBC1D21	TBC1D10A	Q9BXI6	564
TBC1D21	TBC1D7	Q9P0N9	557
TBC1D21	TBC1D22A	Q8WUA7	542
TBC1D21	TBC1D8B	Q0IIM8	540
TBC1D21	TBC1D8	O95759	530
TBC1D21	TBC1D12	O60347	526
TBC1D21	TBC1D2B	Q9UPU7	523
TBC1D21	TBC1D9B	Q66K14	519

IntAct

100 interactions, top by confidence:

A	B	Type	Score
TBC1D21	KIF26A	psi-mi:“MI:0915”(physical association)	0.600
KIF26A	TBC1D21	psi-mi:“MI:0915”(physical association)	0.600
TBC1D21	SEPTIN2	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	EVI5L	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	TCF12	psi-mi:“MI:0915”(physical association)	0.560
GFAP	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
KRT15	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	SNX7	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	KRT35	psi-mi:“MI:0915”(physical association)	0.560
REL	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
KRT40	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
KRT38	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
GTF2E1	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	RAB3IP	psi-mi:“MI:0915”(physical association)	0.560
PMF1	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	RIBC1	psi-mi:“MI:0915”(physical association)	0.560
LCN2	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
GAS2	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
TIMM10	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	SAMD4A	psi-mi:“MI:0915”(physical association)	0.560
TBC1D21	CFAP53	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560
PDCD2	TBC1D21	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (33): TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid), TBC1D21 (Two-hybrid)

ESM2 similar proteins: A1A5K6, A3KGB4, A6H8I2, A8E7G4, A8XSV3, B0R0W9, D3ZGS3, F1QRX7, F6UMY3, F8VPZ3, H2KZZ6, I2HAA0, O43048, O95759, P26448, P36618, Q01968, Q09445, Q0IIM8, Q0P5W1, Q19317, Q2KI13, Q3UYK3, Q55EP9, Q5E9C4, Q5SVR0, Q5ZLD2, Q68F70, Q6NTN5, Q6NU25, Q6NVF0, Q6P6R7, Q6ZT07, Q7T2D0, Q8BH88, Q8IYX1, Q8N3P4, Q8NFA0, Q8TC07, Q8TEU7

Diamond homologs: Q8IYX1, Q9D9D3, Q94BY9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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
Formation of the cornified envelope	5	23.1×	1e-04
Keratinization	5	14.7×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	5	66.1×	8e-07
intermediate filament organization	6	55.6×	1e-07
epithelial cell differentiation	5	33.8×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2013 predictions. Top by Δscore:

Variant	Effect	Δscore
15:73881745:G:GT	donor_gain	1.0000
15:73884147:ACAGG:A	acceptor_loss	1.0000
15:73884148:CAGG:C	acceptor_loss	1.0000
15:73884149:A:AG	acceptor_gain	1.0000
15:73884150:G:GA	acceptor_loss	1.0000
15:73884150:G:GG	acceptor_gain	1.0000
15:73884150:GGAA:G	acceptor_gain	1.0000
15:73884241:CATTG:C	donor_gain	1.0000
15:73884242:ATTG:A	donor_gain	1.0000
15:73884243:TTG:T	donor_gain	1.0000
15:73884244:TG:T	donor_gain	1.0000
15:73884245:GG:G	donor_gain	1.0000
15:73884245:GGT:G	donor_loss	1.0000
15:73884246:G:GG	donor_gain	1.0000
15:73884767:T:A	acceptor_gain	1.0000
15:73884774:A:AG	acceptor_gain	1.0000
15:73884775:A:G	acceptor_gain	1.0000
15:73884777:CTA:C	acceptor_loss	1.0000
15:73884778:TAGC:T	acceptor_loss	1.0000
15:73884779:A:AG	acceptor_gain	1.0000
15:73884779:AGCA:A	acceptor_loss	1.0000
15:73884780:G:GG	acceptor_gain	1.0000
15:73884780:GC:G	acceptor_gain	1.0000
15:73884780:GCA:G	acceptor_gain	1.0000
15:73884780:GCAC:G	acceptor_gain	1.0000
15:73884888:GCAG:G	donor_gain	1.0000
15:73884889:CAGGT:C	donor_loss	1.0000
15:73884890:AGG:A	donor_loss	1.0000
15:73884891:GGTG:G	donor_loss	1.0000
15:73884893:T:A	donor_loss	1.0000

AlphaMissense

2266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:73881432:T:A	W32R	0.991
15:73881432:T:C	W32R	0.991
15:73881674:T:A	W67R	0.991
15:73881674:T:C	W67R	0.991
15:73886611:A:T	E259V	0.986
15:73881434:G:C	W32C	0.984
15:73881434:G:T	W32C	0.984
15:73881664:G:C	R63S	0.984
15:73881664:G:T	R63S	0.984
15:73886550:T:A	W239R	0.984
15:73886550:T:C	W239R	0.984
15:73886607:T:A	W258R	0.982
15:73886607:T:C	W258R	0.982
15:73881723:G:C	R83P	0.981
15:73888467:T:C	L311P	0.981
15:73887666:C:A	A275D	0.978
15:73886554:T:C	F240S	0.977
15:73887678:T:C	L279P	0.977
15:73886127:T:C	L210P	0.976
15:73886605:T:C	L257P	0.976
15:73886610:G:A	E259K	0.975
15:73886565:T:C	F244L	0.974
15:73886567:C:A	F244L	0.974
15:73886567:C:G	F244L	0.974
15:73888479:C:A	A315D	0.971
15:73881663:G:C	R63T	0.970
15:73881676:G:C	W67C	0.970
15:73881676:G:T	W67C	0.970
15:73886553:T:C	F240L	0.969
15:73886555:C:A	F240L	0.969

dbSNP variants (sampled 300 via entrez): RS1000055982 (15:73903017 T>C), RS1000062051 (15:73897244 T>C), RS1000076726 (15:73888364 T>A), RS1000106598 (15:73902759 G>A), RS1000274750 (15:73909484 A>G), RS1000423060 (15:73907649 C>T), RS1000451399 (15:73895934 A>G), RS1000509443 (15:73892708 T>C), RS1000616721 (15:73898315 G>A), RS1000687412 (15:73886932 C>A,T), RS1000688563 (15:73896946 G>A), RS1000715823 (15:73872547 G>A,C,T), RS1000754626 (15:73885722 G>T), RS1000814241 (15:73880875 C>G,T), RS1000850178 (15:73890016 TACAC>T,TAC,TACACAC)

Disease associations

OMIM: gene MIM:620387 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002486_1	Exfoliation glaucoma or exfoliation syndrome	2.000000e-16
GCST002726_4	Glucose homeostasis traits	7.000000e-08
GCST006947_18	Feeling fed-up	8.000000e-09
GCST008059_242	Estimated glomerular filtration rate	6.000000e-10
GCST010108_17	Coffee consumption (cups per day)	3.000000e-08
GCST011741_43	LDL cholesterol levels in HIV infection	1.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0006782	cups of coffee per day measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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