CLN5

Summary

CLN5 (CLN5 lysosomal BMP synthase, HGNC:2076) is a protein-coding gene on chromosome 13q22.3, encoding Bis(monoacylglycero)phosphate synthase CLN5 (O75503). Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via transacylation of 2 molecules of lysophosphatidylglycerol (LPG).

This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.

Source: NCBI Gene 1203 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 730 total — 62 pathogenic, 60 likely-pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_006493

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2076
Approved symbol	CLN5
Name	CLN5 lysosomal BMP synthase
Location	13q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000102805
Ensembl biotype	protein_coding
OMIM	608102
Entrez	1203

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000377453, ENST00000485938, ENST00000616833, ENST00000635761, ENST00000635905, ENST00000635915, ENST00000635989, ENST00000636183, ENST00000636405, ENST00000636520, ENST00000636525, ENST00000636602, ENST00000636681, ENST00000636705, ENST00000636767, ENST00000636780, ENST00000637278, ENST00000637397, ENST00000637537

RefSeq mRNA: 2 — MANE Select: NM_006493 NM_001366624, NM_006493

CCDS: CCDS91815, CCDS9456

Canonical transcript exons

ENST00000377453 — 4 exons

Exon	Start	End
ENSE00000684230	76995902	76996127
ENSE00003712901	76992081	76992271
ENSE00003724627	76995063	76995228
ENSE00003903672	77000458	77005117

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 95.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.8979 / max 135.7973, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135497	23.1328	1803
135498	2.6771	1306
135499	0.0879	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left lobe of thyroid gland	UBERON:0001120	95.61	gold quality
right lobe of thyroid gland	UBERON:0001119	95.48	gold quality
thyroid gland	UBERON:0002046	95.46	gold quality
pericardium	UBERON:0002407	94.42	gold quality
renal medulla	UBERON:0000362	94.15	gold quality
calcaneal tendon	UBERON:0003701	93.94	gold quality
adrenal tissue	UBERON:0018303	92.75	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.74	gold quality
islet of Langerhans	UBERON:0000006	92.67	gold quality
popliteal artery	UBERON:0002250	92.42	gold quality
tibial artery	UBERON:0007610	92.41	gold quality
gall bladder	UBERON:0002110	92.32	gold quality
saphenous vein	UBERON:0007318	92.10	gold quality
tibial nerve	UBERON:0001323	91.79	gold quality
nephron tubule	UBERON:0001231	91.71	gold quality
right uterine tube	UBERON:0001302	91.67	gold quality
stromal cell of endometrium	CL:0002255	91.66	gold quality
aorta	UBERON:0000947	91.63	gold quality
left ovary	UBERON:0002119	91.58	gold quality
trigeminal ganglion	UBERON:0001675	91.49	gold quality
corpus epididymis	UBERON:0004359	91.44	gold quality
left coronary artery	UBERON:0001626	91.23	gold quality
superior surface of tongue	UBERON:0007371	91.15	gold quality
descending thoracic aorta	UBERON:0002345	90.91	gold quality
ascending aorta	UBERON:0001496	90.79	gold quality
thoracic aorta	UBERON:0001515	90.78	gold quality
right ovary	UBERON:0002118	90.72	gold quality
cortex of kidney	UBERON:0001225	90.43	gold quality
right coronary artery	UBERON:0001625	90.41	gold quality
coronary artery	UBERON:0001621	90.36	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-106540	yes	159.37
E-ANND-3	yes	8.22
E-MTAB-7606	no	137.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting CLN5, 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-3925-3P	100.00	69.95	1237
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-7158-5P	99.25	67.95	796

Literature-anchored findings (GeneRIF, showing 30)

• biosynthesis and intracellular localization of this protein (PMID:11971870)
• juvenile and variant late infantile neuronal ceroid lipofuscinoses have mutated CLN genes encoding lysosomal proteins (review) (PMID:12125809)
• Data show that three neuronal ceroid lipofuscinoses disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins (PMID:12134079)
• A novel missense mutation in CLN5 was found in a Colombian family with juvenile-onset neuronal ceroid lipofuscinosis: c. 1627G>A causing Arg112His. (PMID:15728307)
• The CLN5/mRNA expression level reduced to 45% supports the existence of one mRNA non-producing allele, further noticeable at the protein level. (PMID:16814585)
• Reports two sibs harbouring a novel mutation (p.Tyr258Asp) in the CLN5 gene and displaying behaviour disturbances and mental deterioration, rather than epilepsy, as the dominant disease manifestation at onset. (PMID:17607606)
• In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA (PMID:19174516)
• Double immunofluorescence microscopy showed that while the wild-type CLN5 protein is localized in lysosomes, both mutant CLN5 proteins are retained in the endoplasmic reticulum rather than reaching the lysosome. (PMID:19309691)
• Study found that CLN5 interacts with several other NCL proteins namely, CLN1/PPT1, CLN2/TPP1, CLN3, CLN6 and CLN8. (PMID:19941651)
• analysis of mutations in neuronal ceroid lipofuscinosis protein CLN5 (PMID:20052765)
• CLN5 mutations are 1) more common in patients with neuronal ceroid lipofuscinosis (NCL) than previously reported, 2) found in patients of broad ethnic diversity, and 3) can be identified in patients with disease onset in adult and juvenile epochs (PMID:20157158)
• a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome (PMID:22431521)
• This study highlights a close interaction between CLN5/CLN8 proteins, and their role in sphingolipid metabolism. Our findings suggest that CLN5p/CLN8p most likely are positive modulators of CerS1 and/or CerS2. (PMID:23160995)
• There are functional differences in various N-glycosylation sites of CLN5 which affect folding, trafficking, and lysosomal function of CLN5. (PMID:24058541)
• findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders (PMID:25359263)
• Two forms of CLN5, derived from the C-terminal proteolytic processing, are present in most cells and tissues. (PMID:26342652)
• We conclude that, whereas sleep homeostasis is present in CLN5(-/-) sheep, underlying CLN5(-/-) disease processes prevent its full expression, even at early stages. (PMID:27488642)
• Genotype-phenotype correlation between CNL5 gene mutations and CNL5 disease symptoms. (PMID:28542837)
• We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with Alzheimer’s disease. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5’s normal cellular location. (PMID:30037983)
• The onset of visual deficits was much delayed. Computed tomography and MRI showed that brain structures and volumes remained stable. Because gene therapy in humans is more likely to begin after clinical diagnosis, self-complementary AAV9-CLN5 was injected into the brain ventricles of four 7-month-old affected sheep already showing early clinical signs in a second trial. (PMID:30078766)
• This study demonstrated that Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis. (PMID:30264640)
• The Neuronal Ceroid Lipofuscinoses-Linked Loss of Function CLN5 and CLN8 Variants Disrupt Normal Lysosomal Function. (PMID:30919163)
• Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis. (PMID:32302805)
• This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics (PMID:32393339)
• CLN5 in heterozygosis may protect against the development of tumors in a VHL patient. (PMID:32487141)
• Association of the Recurrent Rare Variant c.415T>C p.Phe139Leu in CLN5 With a Recessively Inherited Macular Dystrophy. (PMID:33507209)
• Deficiency of the Lysosomal Protein CLN5 Alters Lysosomal Function and Movement. (PMID:34680045)
• Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. (PMID:35427157)
• Lysosomal dysfunction, autophagic defects, and CLN5 accumulation underlie the pathogenesis of KCTD7-mutated neuronal ceroid lipofuscinoses. (PMID:36368077)
• The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase. (PMID:37708259)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cln5	ENSDARG00000076339
mus_musculus	Cln5	ENSMUSG00000022125
rattus_norvegicus	AABR07008608.1	ENSRNOG00000055439
rattus_norvegicus	AABR07019209.2	ENSRNOG00000062279

Protein

Protein identifiers

Bis(monoacylglycero)phosphate synthase CLN5 — O75503 (reviewed: O75503)

Alternative names: Ceroid-lipofuscinosis neuronal protein 5, Palmitoyl protein thioesterase CLN5, S-depalmitoylase CLN5

All UniProt accessions (10): O75503, A0A087WZY0, A0A1B0GTR6, A0A1B0GTV7, A0A1B0GU14, A0A1B0GUE8, A0A1B0GV94, A0A1B0GVL0, A0A1B0GWI2, A0A1C7CYZ2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via transacylation of 2 molecules of lysophosphatidylglycerol (LPG). BMP also known as lysobisphosphatidic acid plays a key role in the formation of intraluminal vesicles and in maintaining intracellular cholesterol homeostasis. Can use only LPG as the exclusive lysophospholipid acyl donor for base exchange and displays BMP synthase activity towards various LPGs (LPG 14:0, LPG 16:0, LPG 18:0, LPG 18:1) with a higher preference for longer chain lengths. Plays a role in influencing the retrograde trafficking of lysosomal sorting receptors SORT1 and IGF2R from the endosomes to the trans-Golgi network by controlling the recruitment of retromer complex to the endosomal membrane. Regulates the localization and activation of RAB7A which is required to recruit the retromer complex to the endosomal membrane. Exhibits palmitoyl protein thioesterase (S-depalmitoylation) activity in vitro and most likely plays a role in protein S-depalmitoylation.

Subunit / interactions. Multimer. Interacts with SORT1, RAB5A and RAB7A. Interacts with PPT1, TPP1, CLN3, CLN6, CLN8, ATP5F1A and ATP5F1B.

Subcellular location. Lysosome Membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. N-glycosylated with both high mannose and complex type sugars. Glycosylation is important for proper folding and trafficking to the lysosomes. The type II membrane signal anchor is proteolytically cleaved to produce a mature form that is transported to the lysosomes (Bis(monoacylglycero)phosphate synthase CLN5, secreted form). Can undergo proteolytic cleavage at the C-terminus, probably by a cysteine protease and may involve the removal of approximately 10-15 residues from the C-terminal end.

Disease relevance. Ceroid lipofuscinosis, neuronal, 5 (CLN5) [MIM:256731] A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment patterns observed most often in neuronal ceroid lipofuscinosis type 5 comprise mixed combinations of granular, curvilinear, and fingerprint profiles. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Anionic phospholipids activate bis(monoacylglycero)phosphate (BMP) synthase activity. Amiodarone, a cationic amphiphilic drug inhibits BMP synthase activity towards liposomal lysophosphatidylglycerol. Palmostatin B inhibits palmitoyl protein thioesterase activity.

Similarity. Belongs to the CLN5 family.

RefSeq proteins (2): NP_001353553, NP_006484* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026138	CLN5	Family

Pfam: PF15014

Catalyzed reactions (Rhea), 6 shown:

• S-hexadecanoyl-L-cysteinyl-[protein] + H2O = L-cysteinyl-[protein] + hexadecanoate + H(+) (RHEA:19233)
• 2 1-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1’-sn-glycerol) = 1-(9Z-octadecenoyl)-sn-glycero-3-phospho-(3’-(9Z-octadecenoyl)-1’-sn-glycerol) + sn-glycero-3-phospho-(1’-sn-glycerol) (RHEA:77599)
• 2 1-octadecanoyl-sn-glycero-3-phospho-(1’-sn-glycerol) = 1-octadecanoyl-sn-glycero-3-phospho-(3’-octadecanoyl-1’-sn-glycerol) + sn-glycero-3-phospho-(1’-sn-glycerol) (RHEA:77603)
• 2 1-hexadecanoyl-sn-glycero-3-phospho-(1’-sn-glycerol) = 1-hexadecanoyl-sn-glycero-3-phospho-(3’-hexadecanoyl-1’-sn-glycerol) + sn-glycero-3-phospho-(1’-sn-glycerol) (RHEA:77607)
• 2 1-tetradecanoyl-sn-glycero-3-phospho-(1’-sn-glycerol) = 1-tetradecanoyl-sn-glycero-3-phospho-(3’-tetradecanoyl-1’-sn-glycerol) + sn-glycero-3-phospho-(1’-sn-glycerol) (RHEA:77611)
• 2 1-acyl-sn-glycero-3-phospho-(1’-sn-glycerol) = 1-acyl-sn-glycero-3-phospho-(3’-acyl-sn-1’-glycerol) + sn-glycero-3-phospho-(1’-sn-glycerol) (RHEA:77619)

UniProt features (51 total): sequence variant 16, mutagenesis site 14, glycosylation site 8, chain 2, disulfide bond 2, topological domain 2, sequence conflict 2, active site 2, transmembrane region 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6R99	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75503-F1	83.05	0.65

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 (3): 117 (proton acceptor); 231 (nucleophile; acyl-thioester intermediate); 43–44 (cleavage; by sppl3)

Disulfide bonds (2): 70–159, 77–165

Glycosylation sites (8): 143, 178, 203, 255, 271, 281, 352, 130

Mutagenesis-validated functional residues (14):

Position	Phenotype
101	significant decrease in palmitoyl protein thioesterase activity.
115	significant decrease in palmitoyl protein thioesterase activity.
117	significant decrease in palmitoyl protein thioesterase activity.
130	loss of glycosylation. retained in the endoplasmic reticulum rather than reaching the lysosome.
143	loss of glycosylation. effectively transported to the lysosome.
178	loss of glycosylation. effectively transported to the lysosome.
203	loss of glycosylation. retained in the endoplasmic reticulum rather than reaching the lysosome.
231	significant decrease in bis(monoacylglycero)phosphate synthase and palmitoyl protein thioesterase activities. no alterat
255	loss of glycosylation. retained in the endoplasmic reticulum rather than reaching the lysosome.
259	significant decrease in palmitoyl protein thioesterase activity.
271	loss of glycosylation. retained in the endoplasmic reticulum rather than reaching the lysosome.
281	loss of glycosylation. partially retained in the endoplasmic reticulum.
318–319	weakens vesicular bis(monoacylglycero)phosphate binding. no alterations in secondary structure and thermal stability.
352	loss of glycosylation. retained in the golgi apparatus rather than reaching the lysosome.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 234 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_NEURON_MATURATION, GOBP_MACROMOLECULE_DEACYLATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, CEBPB_01, GOBP_POSITIVE_REGULATION_OF_BINDING, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_ANATOMICAL_STRUCTURE_MATURATION, CATRRAGC_UNKNOWN, GOBP_PROTEIN_MATURATION

GO Biological Process (11): obsolete signal peptide processing (GO:0006465), lysosome organization (GO:0007040), lysosomal lumen acidification (GO:0007042), brain development (GO:0007420), visual perception (GO:0007601), neurogenesis (GO:0022008), protein catabolic process (GO:0030163), retrograde transport, endosome to Golgi (GO:0042147), neuron maturation (GO:0042551), positive regulation of GTP binding (GO:1904426), obsolete glycosylation (GO:0070085)

GO Molecular Function (8): D-mannose binding (GO:0005537), palmitoyl-(protein) hydrolase activity (GO:0008474), hydrolase activity, acting on glycosyl bonds (GO:0016798), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), bis(monoacylglycero)phosphate synthase activity (GO:0160121), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (9): lysosome (GO:0005764), lysosomal membrane (GO:0005765), vacuolar lumen (GO:0005775), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	3
catalytic activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
lytic vacuole organization	1
vacuolar acidification	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
nervous system development	1
cell differentiation	1
macromolecule catabolic process	1
protein metabolic process	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
cell maturation	1
neuron development	1
GTP binding	1
positive regulation of binding	1
monosaccharide binding	1
thiolester hydrolase activity	1
palmitoyl hydrolase activity	1
catalytic activity, acting on a protein	1
hydrolase activity	1
fatty acyl-CoA hydrolase activity	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
binding	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
vacuole	1
intracellular organelle lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLN5	CLN3	Q13286	996
CLN5	CLN6	Q9NWW5	982
CLN5	PPT1	P50897	978
CLN5	CLN8	Q9UBY8	974
CLN5	MFSD8	Q8NHS3	938
CLN5	DNAJC5	Q9H3Z4	837
CLN5	BTF3	P20290	810
CLN5	CTSD	P07339	804
CLN5	KCTD7	Q96MP8	790
CLN5	TPP1	O14773	767
CLN5	PPT2	Q9UMR5	758
CLN5	CTSF	Q9UBX1	692
CLN5	ATP13A2	Q9NQ11	671
CLN5	POU4F1	Q01851	593
CLN5	AGA	P20933	592

IntAct

44 interactions, top by confidence:

A	B	Type	Score
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
	CLN5	psi-mi:“MI:0915”(physical association)	0.560
CLN5	SLC41A1	psi-mi:“MI:0915”(physical association)	0.560
CLN5	PLPP6	psi-mi:“MI:0915”(physical association)	0.560
CLN5	IGF2	psi-mi:“MI:0915”(physical association)	0.560
CLN5	SLC41A2	psi-mi:“MI:0915”(physical association)	0.560
CLN5	GPR152	psi-mi:“MI:0915”(physical association)	0.560
CLN5	FDFT1	psi-mi:“MI:0915”(physical association)	0.560
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CLN5	CLN3	psi-mi:“MI:0915”(physical association)	0.520
Dlg4	CLN5	psi-mi:“MI:0407”(direct interaction)	0.440
CLN5		psi-mi:“MI:0915”(physical association)	0.400
CLN5	PROM1	psi-mi:“MI:0915”(physical association)	0.370
CLEC3A	ZNF593	psi-mi:“MI:0914”(association)	0.350
CALR3	CLN5	psi-mi:“MI:0914”(association)	0.350
OBP2A	CLN5	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
RLN1	RTL8C	psi-mi:“MI:0914”(association)	0.350
SPX	ERI3	psi-mi:“MI:0914”(association)	0.350
CLN5	ADGRL1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SLURP1	MAN2B1	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
KRT8	CLN5	psi-mi:“MI:0915”(physical association)	0.000
CLN5		psi-mi:“MI:0915”(physical association)	0.000
SLC41A1	CLN5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (75): CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS), CLN5 (Affinity Capture-MS)

ESM2 similar proteins: A0A075TR41, A0A1J0HSL4, A0A1L9WN23, A0A2P1DP82, A0A364LXP7, A1CFL7, A5DV96, B0XQY0, B6HRA4, B8NT06, C5E2Q0, C5GAC6, C5JJY8, C8VCL4, E9QSG0, G1XTZ8, G2WWH6, G3Y423, I1RQE2, J4VSL0, J5J930, J9VG42, O74505, O75503, P0CM26, P0CM27, P0CO40, P0CO41, P0CP18, P0CP19, P0CS68, P0CS69, P23710, Q01285, Q08912, Q08989, Q0CJ58, Q0CSY3, Q4IA62, Q4IMZ7

Diamond homologs: A2TJ54, O75503, Q1ZYR0, Q3UMW8, Q5JZQ9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
Neutrophil degranulation	6	6.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	60
Uncertain significance	255
Likely benign	253
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069801	NM_006493.4(CLN5):c.84_96dup (p.Leu33fs)	Pathogenic
1071340	NM_006493.4(CLN5):c.827_828del (p.Phe276fs)	Pathogenic
1073281	NM_006493.4(CLN5):c.812del (p.Asn271fs)	Pathogenic
1075607	NM_006493.4(CLN5):c.580C>T (p.Gln194Ter)	Pathogenic
1180754	NM_006493.4(CLN5):c.174-1G>A	Pathogenic
1351290	NM_006493.4(CLN5):c.251_252del (p.Pro84fs)	Pathogenic
1420350	NM_006493.4(CLN5):c.627T>G (p.Tyr209Ter)	Pathogenic
1425365	NM_006493.4(CLN5):c.404G>A (p.Trp135Ter)	Pathogenic
1451889	NM_006493.4(CLN5):c.956_957del (p.Lys319fs)	Pathogenic
1452241	NM_006493.4(CLN5):c.679del (p.Asp227fs)	Pathogenic
1454215	NM_006493.4(CLN5):c.599_600insCA (p.Lys200fs)	Pathogenic
1458984	NM_006493.4(CLN5):c.168del (p.Tyr57fs)	Pathogenic
2004384	NM_006493.4(CLN5):c.764dup (p.Asn255fs)	Pathogenic
2035261	NM_006493.4(CLN5):c.687C>G (p.Tyr229Ter)	Pathogenic
2036621	NM_006493.4(CLN5):c.1014del (p.Phe338fs)	Pathogenic
205144	NM_006493.4(CLN5):c.448C>T (p.Arg150Ter)	Pathogenic
2090100	NM_006493.4(CLN5):c.623_627del (p.Ile207_Tyr208insTer)	Pathogenic
2095804	NM_006493.4(CLN5):c.786C>G (p.Tyr262Ter)	Pathogenic
2103526	NM_006493.4(CLN5):c.242C>A (p.Ser81Ter)	Pathogenic
2113602	NM_006493.4(CLN5):c.653dup (p.Glu219fs)	Pathogenic
2435733	NM_006493.4(CLN5):c.639_640insTT (p.Val214fs)	Pathogenic
253413	GRCh37/hg19 13q22.3(chr13:77574552-77575350)x1	Pathogenic
2564	NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer)	Pathogenic
2565	NM_006493.4(CLN5):c.78G>A (p.Trp26Ter)	Pathogenic
2568	NM_006493.4(CLN5):c.907G>T (p.Glu303Ter)	Pathogenic
2571	NM_006493.4(CLN5):c.566-42_*46del	Pathogenic
2694563	NM_006493.4(CLN5):c.989G>A (p.Trp330Ter)	Pathogenic
2710995	NM_006493.4(CLN5):c.216del (p.Lys73fs)	Pathogenic
2743254	NM_006493.4(CLN5):c.768T>G (p.Tyr256Ter)	Pathogenic
2743639	NM_006493.4(CLN5):c.109del (p.Val37fs)	Pathogenic

SpliceAI

1214 predictions. Top by Δscore:

Variant	Effect	Δscore
13:76995058:ATTAG:A	acceptor_gain	1.0000
13:76995059:TTA:T	acceptor_loss	1.0000
13:76995060:TAGGC:T	acceptor_loss	1.0000
13:76995061:A:AG	acceptor_gain	1.0000
13:76995061:AG:A	acceptor_gain	1.0000
13:76995062:G:A	acceptor_loss	1.0000
13:76995062:G:GG	acceptor_gain	1.0000
13:76995062:GG:G	acceptor_gain	1.0000
13:76995062:GGC:G	acceptor_gain	1.0000
13:76995225:CTTG:C	donor_gain	1.0000
13:76995226:TTGG:T	donor_loss	1.0000
13:76995227:TGGT:T	donor_loss	1.0000
13:76995228:GGTA:G	donor_loss	1.0000
13:76995229:G:GC	donor_loss	1.0000
13:76995229:G:GG	donor_gain	1.0000
13:76995230:T:A	donor_loss	1.0000
13:76995234:G:GT	donor_gain	1.0000
13:77007790:T:C	acceptor_gain	1.0000
13:77015404:CATA:C	donor_loss	1.0000
13:77015405:ATAC:A	donor_loss	1.0000
13:77015406:TAC:T	donor_loss	1.0000
13:77015407:A:AG	donor_loss	1.0000
13:77015408:C:CT	donor_loss	1.0000
13:77015408:CCTG:C	donor_gain	1.0000
13:77015576:TGAGA:T	acceptor_gain	1.0000
13:77015577:GAGA:G	acceptor_gain	1.0000
13:77015578:AGA:A	acceptor_gain	1.0000
13:77015579:GA:G	acceptor_gain	1.0000
13:77015579:GACTG:G	acceptor_loss	1.0000
13:77015581:C:CC	acceptor_gain	1.0000

AlphaMissense

2362 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:76995965:T:A	W135R	0.999
13:76995965:T:C	W135R	0.999
13:77000526:T:A	W212R	0.999
13:77000526:T:C	W212R	0.999
13:76995967:G:C	W135C	0.998
13:76995967:G:T	W135C	0.998
13:76996034:T:A	W158R	0.998
13:76996034:T:C	W158R	0.998
13:76996036:G:C	W158C	0.998
13:76996036:G:T	W158C	0.998
13:76996087:G:C	W175C	0.998
13:76996087:G:T	W175C	0.998
13:77000679:A:C	S263R	0.998
13:77000681:T:A	S263R	0.998
13:77000681:T:G	S263R	0.998
13:76995118:T:C	C77R	0.997
13:76995917:G:C	A119P	0.997
13:76995993:G:A	C144Y	0.997
13:76995994:T:G	C144W	0.997
13:76996037:T:A	C159S	0.997
13:76996038:G:C	C159S	0.997
13:76996085:T:A	W175R	0.997
13:76996085:T:C	W175R	0.997
13:77000584:G:A	C231Y	0.997
13:76995097:T:A	C70S	0.996
13:76995098:G:C	C70S	0.996
13:76995193:T:A	W102R	0.996
13:76995193:T:C	W102R	0.996
13:76996037:T:C	C159R	0.996
13:76996055:T:C	C165R	0.996

dbSNP variants (sampled 300 via entrez): RS1000253633 (13:76998359 A>G,T), RS1000385170 (13:76992406 C>G), RS1000498835 (13:76997186 G>A,T), RS1000591645 (13:76997379 C>T), RS1000628150 (13:76998718 G>C), RS1000749476 (13:76991031 A>G), RS1000987293 (13:76997123 C>T), RS1001016373 (13:77003891 G>A), RS1001047529 (13:77003582 T>A,C), RS1001169898 (13:77003797 A>C), RS1001726574 (13:77003236 C>G), RS1001869363 (13:76997917 T>C), RS1001886162 (13:76991370 G>C,T), RS1002150656 (13:76997648 T>A), RS1002331160 (13:77004362 C>T)

Disease associations

OMIM: gene MIM:608102 | disease phenotypes: MIM:256730, MIM:256731, MIM:613811

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis 5	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Mondo (6): neuronal ceroid lipofuscinosis (MONDO:0016295), neuronal ceroid lipofuscinosis 5 (MONDO:0009745), inherited retinal dystrophy (MONDO:0019118), neurodevelopmental disorder (MONDO:0700092), pontocerebellar hypoplasia type 2D (MONDO:0013438), intellectual disability (MONDO:0001071)

Orphanet (8): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN5 disease (Orphanet:228360), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Progressive cerebello-cerebral atrophy (Orphanet:247198), Pontocerebellar hypoplasia type 2 (Orphanet:2524), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000529	Progressive visual loss
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001311	Abnormal nervous system electrophysiology
HP:0001336	Myoclonus
HP:0001922	Vacuolated lymphocytes
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002075	Dysdiadochokinesis
HP:0002120	Cerebral cortical atrophy
HP:0002312	Clumsiness
HP:0002333	Motor deterioration
HP:0002376	Developmental regression
HP:0002505	Loss of ambulation
HP:0003205	Curvilinear intracellular accumulation of autofluorescent lipopigment storage material
HP:0003208	Fingerprint intracellular accumulation of autofluorescent lipopigment storage material
HP:0003226	Rectilinear intracellular accumulation of autofluorescent lipopigment storage material
HP:0003621	Juvenile onset
HP:0200085	Limb tremor
HP:0000556	Retinal dystrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002682_13	Tourette’s syndrome or obsessive-compulsive disorder	1.000000e-06
GCST003429_16	Morning vs. evening chronotype	4.000000e-08
GCST006585_1725	Blood protein levels	1.000000e-10
GCST012304_3	Major depressive disorder	2.000000e-06

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D058499	Retinal Dystrophies	C11.768.585.658
C575534	Ceroid lipofuscinosis, neuronal 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	decreases expression, increases expression	2
dicrotophos	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
jinfukang	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Gallic Acid	decreases expression	1
Ivermectin	decreases expression	1
Ketoconazole	affects expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1

Cellosaurus cell lines

7 cell lines: 5 induced pluripotent stem cell, 1 embryonic stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6T1	UCLi021-A	Induced pluripotent stem cell	Female
CVCL_C6T2	UCLi022-A	Induced pluripotent stem cell	Male
CVCL_E4QM	KOLF2.1J CLN5 W26X SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E4QN	KOLF2.1J CLN5 W26X SNV/WT	Induced pluripotent stem cell	Male
CVCL_E4QP	KOLF2.1J CLN5 9.1kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_F0PN	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) CLN5-/-	Embryonic stem cell	Female
CVCL_XM83	HAP1 CLN5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database