GMCL2

Summary

GMCL2 (germ cell-less 2, spermatogenesis associated, HGNC:19717) is a protein-coding gene on chromosome 5q35.3, encoding Germ cell-less protein-like 2 (Q8NEA9). Possible function in spermatogenesis.

This locus shares a high degree of identity with the multi-exon germ cell-less gene on chromosome 2. Despite its single-exon nature, this chromosome 5 locus contains an open reading frame that could putatively encode a full-length germ cell-less related protein.

Source: NCBI Gene 64396 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• MANE Select transcript: NM_001358008

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19717
Approved symbol	GMCL2
Name	germ cell-less 2, spermatogenesis associated
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	GCL
Ensembl gene	ENSG00000244234
Ensembl biotype	protein_coding
OMIM	618629
Entrez	64396

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000463439

RefSeq mRNA: 1 — MANE Select: NM_001358008 NM_001358008

CCDS: CCDS4433

Canonical transcript exons

ENST00000463439 — 1 exons

Exon	Start	End
ENSE00002042522	178184505	178187371

Expression profiles

Bgee: expression breadth tissue_specific, 8 present calls, max score 80.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0108 / max 8.2677, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65155	0.0108	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.97	gold quality
testis	UBERON:0000473	75.81	gold quality
left testis	UBERON:0004533	75.08	gold quality
right testis	UBERON:0004534	74.75	gold quality
ventricular zone	UBERON:0003053	40.00	gold quality
stromal cell of endometrium	CL:0002255	38.91	gold quality
granulocyte	CL:0000094	38.77	gold quality
bone marrow cell	CL:0002092	38.38	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
duodenum	UBERON:0002114	36.87	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
skeletal muscle tissue	UBERON:0001134	36.22	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
liver	UBERON:0002107	35.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.40	gold quality
muscle tissue	UBERON:0002385	34.25	gold quality
bone marrow	UBERON:0002371	34.03	gold quality
right lobe of liver	UBERON:0001114	32.79	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
leukocyte	CL:0000738	30.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	30.42	gold quality
monocyte	CL:0000576	30.26	gold quality
prefrontal cortex	UBERON:0000451	29.96	gold quality
lymph node	UBERON:0000029	28.76	gold quality
urinary bladder	UBERON:0001255	28.62	gold quality
islet of Langerhans	UBERON:0000006	27.91	gold quality
muscle of leg	UBERON:0001383	27.90	gold quality
blood	UBERON:0000178	27.84	gold quality
smooth muscle tissue	UBERON:0001135	27.42	gold quality
primary visual cortex	UBERON:0002436	27.36	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.07
E-GEOD-99795	no	0.65

Regulation

Is transcription factor: no

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gmcl1	ENSDARG00000020948
mus_musculus	Gmcl1	ENSMUSG00000001157
rattus_norvegicus	Gmcl1	ENSRNOG00000017838
drosophila_melanogaster	gcl	FBGN0005695
caenorhabditis_elegans		WBGENE00013382

Paralogs (3): GMCL1 (ENSG00000087338), BTBD16 (ENSG00000138152), C10orf120 (ENSG00000183559)

Protein

Protein identifiers

Germ cell-less protein-like 2 — Q8NEA9 (reviewed: Q8NEA9)

Alternative names: Germ cell-less protein-like 1-like

All UniProt accessions (1): Q8NEA9

UniProt curated annotations — full annotation on UniProt →

Function. Possible function in spermatogenesis. Probable substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Subunit / interactions. Interacts with CUL3.

Subcellular location. Nucleus matrix.

Tissue specificity. Expressed predominantly in testis.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. According to some authors, GMCL2 is a GMCL retrogene on chromosome 5 which is likely to be functional.

RefSeq proteins (1): NP_001344937* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR043380	Gcl-like	Family

Pfam: PF00651

UniProt features (14 total): sequence conflict 7, short sequence motif 2, chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEA9-F1	82.95	0.69

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 23 (showing top): GOBP_MALE_GAMETE_GENERATION, CTATGCA_MIR153, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, NUYTTEN_NIPP1_TARGETS_DN, GOMF_CULLIN_FAMILY_PROTEIN_BINDING, CDC5_01, ZNF618_TARGET_GENES, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_CONJUGATION, TGACAGNY_MEIS1_01, TTANTCA_UNKNOWN, MYOCD_TARGET_GENES, STAT5A_04

GO Biological Process (4): germ cell development (GO:0007281), spermatogenesis (GO:0007283), protein ubiquitination (GO:0016567), cell differentiation (GO:0030154)

GO Molecular Function (2): cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), nuclear matrix (GO:0016363)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	2
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
male gamete generation	1
protein modification by small protein conjugation	1
cellular developmental process	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GMCL2	KIF4B	Q2VIQ3	494
GMCL2	CDC14B	O60729	448
GMCL2	RBMXL1	Q96E39	436
GMCL2	CDC14C	A4D256	434
GMCL2	AVPI1	Q5T686	432
GMCL2	NACA2	Q9H009	432
GMCL2	UTP14C	Q5TAP6	430
GMCL2	FTHL17	Q9BXU8	414
GMCL2	H2AB3	P0C5Z0	390
GMCL2	TAF1L	Q8IZX4	375
GMCL2	ELP2	Q6IA86	358
GMCL2	ACTRT1	Q8TDG2	353
GMCL2	H1-7	Q75WM6	348
GMCL2	TRIM47	Q96LD4	325
GMCL2	SLC4A3	P48751	325

IntAct

97 interactions, top by confidence:

A	B	Type	Score
GAGE5	GMCL2	psi-mi:“MI:0915”(physical association)	0.740
GMCL2	GAGE5	psi-mi:“MI:0915”(physical association)	0.740
GAGE8	GMCL2	psi-mi:“MI:0915”(physical association)	0.700
GMCL2	GAGE8	psi-mi:“MI:0915”(physical association)	0.700
GMCL2	IKZF1	psi-mi:“MI:0915”(physical association)	0.670
IKZF1	GMCL2	psi-mi:“MI:0915”(physical association)	0.670
GAGE12B	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
GMCL2	GAGE12I	psi-mi:“MI:0915”(physical association)	0.560
LIMS4	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
GMCL2	SHQ1	psi-mi:“MI:0915”(physical association)	0.560
GMCL2	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
BHLHE40	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
HNRNPM	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
FLJ13057	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
GMCL2	UBE2I	psi-mi:“MI:0915”(physical association)	0.560
USHBP1	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
LZTS2	GMCL2	psi-mi:“MI:0915”(physical association)	0.560
GMCL2	BCL11A	psi-mi:“MI:0915”(physical association)	0.560
KAT5	GMCL2	psi-mi:“MI:0915”(physical association)	0.560

ESM2 similar proteins: A0A072VIM5, A2AQW0, B5X561, F4JSE7, O04615, O35099, O81916, O82343, O94955, P58544, Q0IY07, Q0JC27, Q10MI4, Q2HW56, Q53NI2, Q5ZJ87, Q66J91, Q6E7H0, Q6PNC0, Q6ZN16, Q7ZX59, Q80WG7, Q84UI6, Q8CFE5, Q8LPQ5, Q8NEA9, Q8S8F2, Q8VYP9, Q8VZF6, Q8W032, Q8W519, Q94BM7, Q99683, Q9BX70, Q9CAJ9, Q9CTN4, Q9FLR0, Q9FNP1, Q9FPW6, Q9FYF9

Diamond homologs: Q01820, Q8NEA9, Q920G9, Q96IK5, Q99N64, Q6NRS1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:178186904:A:C	F132L	0.991
5:178186904:A:T	F132L	0.991
5:178186906:A:G	F132L	0.991
5:178186994:A:C	F102L	0.989
5:178186994:A:T	F102L	0.989
5:178186996:A:G	F102L	0.989
5:178186945:A:G	W119R	0.988
5:178186945:A:T	W119R	0.988
5:178186923:A:G	L126S	0.987
5:178186965:A:G	I112T	0.987
5:178186905:A:G	F132S	0.986
5:178186995:A:G	F102S	0.985
5:178186738:C:G	A188P	0.984
5:178186943:C:A	W119C	0.984
5:178186943:C:G	W119C	0.984
5:178186965:A:C	I112S	0.983
5:178186938:A:G	L121S	0.979
5:178186737:G:T	A188D	0.978
5:178186792:A:C	Y170D	0.977
5:178186936:G:C	H122D	0.976
5:178186815:A:G	L162P	0.975
5:178186934:G:C	H122Q	0.973
5:178186934:G:T	H122Q	0.973
5:178186965:A:T	I112N	0.972
5:178186995:A:C	F102C	0.972
5:178186882:A:G	W140R	0.971
5:178186882:A:T	W140R	0.971
5:178186905:A:C	F132C	0.971
5:178186915:A:G	S129P	0.970
5:178186959:G:T	A114D	0.970

dbSNP variants (sampled 300 via entrez): RS1000973872 (5:178188096 G>A), RS1001691362 (5:178188854 T>A), RS1002142223 (5:178188577 G>T), RS1002716976 (5:178187366 G>A,C,T), RS1002924821 (5:178184139 T>C), RS1003116991 (5:178187599 C>A), RS1005002848 (5:178186093 T>G), RS1005090821 (5:178187207 C>A,G,T), RS1005665723 (5:178188912 G>A,C), RS1007594382 (5:178187713 A>C), RS10075968 (5:178189307 A>C), RS10077612 (5:178189040 T>C), RS1008347060 (5:178184895 T>C), RS1009784733 (5:178188323 T>C), RS1009890435 (5:178188187 TGTGGTG>T,TGTG)

Disease associations

OMIM: gene MIM:618629 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000917_8	Rheumatoid arthritis	4.000000e-06
GCST005991_13	Platelet count	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

1 total (human), top 1 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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