RTL4

Summary

RTL4 (retrotransposon Gag like 4, HGNC:25214) is a protein-coding gene on chromosome Xq23, encoding Retrotransposon Gag-like protein 4 (Q6ZR62). Involved in cognitive function in the brain, possibly via the noradrenergic system.

Predicted to enable nucleic acid binding activity and zinc ion binding activity. Predicted to act upstream of or within cognition and norepinephrine metabolic process.

Source: NCBI Gene 340595 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_001395362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25214
Approved symbol	RTL4
Name	retrotransposon Gag like 4
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	Mart4, Mar4, FLJ46608, SIRH11
Ensembl gene	ENSG00000187823
Ensembl biotype	protein_coding
OMIM	301131
Entrez	340595

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000340433, ENST00000695808, ENST00000695839, ENST00000859811

RefSeq mRNA: 2 — MANE Select: NM_001395362 NM_001004308, NM_001395362

CCDS: CCDS35369

Canonical transcript exons

ENST00000695839 — 5 exons

Exon	Start	End
ENSE00001372642	112454500	112457514
ENSE00003965096	112431114	112431168
ENSE00003965101	112130983	112131101
ENSE00003965179	112083016	112083117
ENSE00003965180	112306361	112306520

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 85.62.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.62	gold quality
liver	UBERON:0002107	52.89	gold quality
right lobe of liver	UBERON:0001114	49.49	gold quality
prefrontal cortex	UBERON:0000451	46.03	gold quality
mucosa of stomach	UBERON:0001199	43.95	gold quality
cortical plate	UBERON:0005343	43.42	gold quality
superior frontal gyrus	UBERON:0002661	42.05	gold quality
adult mammalian kidney	UBERON:0000082	41.84	gold quality
sural nerve	UBERON:0015488	40.70	gold quality
frontal cortex	UBERON:0001870	40.63	gold quality
kidney	UBERON:0002113	40.43	gold quality
primary visual cortex	UBERON:0002436	40.42	gold quality
hypothalamus	UBERON:0001898	39.78	gold quality
metanephros cortex	UBERON:0010533	38.50	gold quality
bone marrow cell	CL:0002092	38.45	gold quality
cerebral cortex	UBERON:0000956	37.98	silver quality
cortex of kidney	UBERON:0001225	37.81	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
granulocyte	CL:0000094	36.21	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
substantia nigra	UBERON:0002038	35.09	silver quality
brain	UBERON:0000955	34.53	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	33.19	gold quality
bone marrow	UBERON:0002371	32.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
calcaneal tendon	UBERON:0003701	31.58	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
putamen	UBERON:0001874	30.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting RTL4, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3679-3P	99.64	69.88	1599

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rtl4	ENSMUSG00000071679
rattus_norvegicus	Rtl4	ENSRNOG00000031638

Paralogs (10): RTL8C (ENSG00000134590), RTL3 (ENSG00000179300), LDOC1 (ENSG00000182195), RTL6 (ENSG00000188636), RTL8A (ENSG00000203950), RTL8B (ENSG00000212747), RTL10 (ENSG00000215012), PEG10 (ENSG00000242265), RTL5 (ENSG00000242732), RTL1 (ENSG00000254656)

Protein

Protein identifiers

Retrotransposon Gag-like protein 4 — Q6ZR62 (reviewed: Q6ZR62)

Alternative names: Mammalian retrotransposon-derived protein 4, Zinc finger CCHC domain-containing protein 16

All UniProt accessions (1): Q6ZR62

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cognitive function in the brain, possibly via the noradrenergic system.

Miscellaneous. RTL4 is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.

RefSeq proteins (2): NP_001004308, NP_001382291* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001878	Znf_CCHC	Domain
IPR032567	RTL1-rel	Family
IPR036875	Znf_CCHC_sf	Homologous_superfamily

UniProt features (4 total): sequence variant 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZR62-F1	49.13	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 28 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, ATGTTAA_MIR302C, chrXq23, GOBP_NOREPINEPHRINE_METABOLIC_PROCESS, MIR3143, MIR4531, MIR4516, MIR5582_5P, MIR2113, MIR4742_3P, MIR5703, MIR4434, MIR548V

GO Biological Process (2): norepinephrine metabolic process (GO:0042415), cognition (GO:0050890)

GO Molecular Function (4): nucleic acid binding (GO:0003676), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
catecholamine metabolic process	1
nervous system process	1
transition metal ion binding	1
cation binding	1

Protein interactions and networks

STRING

402 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTL4	RTL6	Q6ICC9	771
RTL4	RTL9	Q8NET4	716
RTL4	RTL8C	A6ZKI3	675
RTL4	LDOC1	O95751	653
RTL4	RTL1	A6NKG5	628
RTL4	LHFPL1	Q86WI0	613
RTL4	ITGB1	P05556	520
RTL4	RTL5	Q5HYW3	518
RTL4	AMBP	P00977	507
RTL4	RTL8B	Q17RB0	474
RTL4	THY1	P04216	430
RTL4	PEG10	Q86TG7	420
RTL4	ENG	P17813	418
RTL4	NT5E	P21589	404
RTL4	LRRK1	Q38SD2	394

IntAct

4 interactions, top by confidence:

A	B	Type	Score
AGR2	RTL4	psi-mi:“MI:0915”(physical association)	0.560
AGR2	RTL4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): ZCCHC16 (Proximity Label-MS), ZCCHC16 (Two-hybrid), ZCCHC16 (Affinity Capture-MS)

ESM2 similar proteins: A6NKG5, B0BAX9, G2TRT2, O12157, P03161, P03364, P0C2I8, P0C2J2, P0C2J4, P0C2J6, P0C691, P0CX59, P0CX60, P0CX61, P0CX62, P17192, P19558, P22281, P25383, P30028, P61511, P61512, P85051, Q03483, Q03964, Q04215, Q09T00, Q0R5R4, Q12217, Q12260, Q12266, Q12293, Q12391, Q12392, Q12439, Q12470, Q1PD56, Q3URY0, Q4R7E8, Q52QI2

Diamond homologs: Q3URY0, Q6ZR62, Q8N8U3

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	43
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

52 predictions. Top by Δscore:

Variant	Effect	Δscore
X:112455674:A:T	donor_gain	0.9500
X:112455658:G:GG	donor_gain	0.8700
X:112455657:A:AG	donor_gain	0.8600
X:112455673:G:GT	donor_gain	0.8000
X:112456171:GA:G	acceptor_gain	0.7600
X:112455662:G:GT	donor_gain	0.6000
X:112456170:A:AG	acceptor_gain	0.5500
X:112456171:G:GG	acceptor_gain	0.5500
X:112454573:GCT:G	donor_gain	0.4100
X:112457040:T:A	acceptor_gain	0.3700
X:112455465:G:T	acceptor_gain	0.3600
X:112455464:A:T	acceptor_gain	0.3400
X:112456171:G:C	acceptor_gain	0.3400
X:112455663:A:T	donor_gain	0.3300
X:112455463:TAG:T	acceptor_gain	0.3100
X:112456164:C:CT	acceptor_gain	0.3100
X:112456143:CCTA:C	acceptor_gain	0.3000
X:112456145:T:TA	acceptor_gain	0.3000
X:112456146:A:AA	acceptor_gain	0.3000
X:112454605:C:G	donor_gain	0.2900
X:112456158:TA:T	acceptor_gain	0.2900
X:112454683:ACT:A	donor_gain	0.2800
X:112455395:C:T	donor_gain	0.2800
X:112455446:C:CT	acceptor_gain	0.2800
X:112456156:TATA:T	acceptor_gain	0.2700
X:112456159:A:AG	acceptor_loss	0.2700
X:112456160:T:G	acceptor_loss	0.2700
X:112456166:TCCTA:T	acceptor_loss	0.2700
X:112456167:CCTAG:C	acceptor_loss	0.2700
X:112456168:CTAGA:C	acceptor_loss	0.2700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000016562 (X:112383595 T>C), RS1000018535 (X:112228121 C>T), RS1000021966 (X:112107190 A>C,G), RS1000037581 (X:112162514 G>A,C), RS1000061133 (X:112333700 G>A), RS1000063283 (X:112221419 C>T), RS1000069831 (X:112084706 T>A), RS1000077380 (X:112312522 G>C), RS1000085000 (X:112386894 A>T), RS1000133677 (X:112303887 T>C), RS1000137390 (X:112171555 A>C), RS1000138181 (X:112099369 A>G), RS1000139267 (X:112396289 C>G), RS1000153608 (X:112176890 T>A), RS1000154433 (X:112456568 T>C)

Disease associations

OMIM: gene MIM:301131 | 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
GCST000328_12	Biochemical measures	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	decreases methylation	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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