CLN8

Summary

CLN8 (CLN8 transmembrane ER and ERGIC protein, HGNC:2079) is a protein-coding gene on chromosome 8p23.3, encoding Protein CLN8 (Q9UBY8). Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain.

Source: NCBI Gene 2055 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 608 total — 50 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 53
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_018941

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2079
Approved symbol	CLN8
Name	CLN8 transmembrane ER and ERGIC protein
Location	8p23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39417, TLCD6
Ensembl gene	ENSG00000182372
Ensembl biotype	protein_coding
OMIM	607837
Entrez	2055

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 28 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000331222, ENST00000517514, ENST00000518780, ENST00000519254, ENST00000520991, ENST00000523237, ENST00000524258, ENST00000635751, ENST00000635970, ENST00000636605, ENST00000636934, ENST00000637083, ENST00000637156, ENST00000637594, ENST00000859935, ENST00000859936, ENST00000859937, ENST00000859938, ENST00000859939, ENST00000859940, ENST00000859941, ENST00000933685, ENST00000933686, ENST00000933687, ENST00000933688, ENST00000933689, ENST00000933690, ENST00000933691, ENST00000933692, ENST00000965219, ENST00000965220, ENST00000965221, ENST00000965222

RefSeq mRNA: 1 — MANE Select: NM_018941 NM_018941

CCDS: CCDS5956

Canonical transcript exons

ENST00000331222 — 3 exons

Exon	Start	End
ENSE00001289770	1780250	1786570
ENSE00001306327	1763789	1763885
ENSE00001310410	1770932	1771597

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 89.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5812 / max 184.1094, expressed in 1796 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87178	4.8581	1695
87179	4.0913	1548
87173	1.4567	656
87180	1.3723	932
87177	0.4282	217
87176	0.3082	130
87174	0.0664	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	89.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.49	gold quality
stromal cell of endometrium	CL:0002255	86.06	gold quality
monocyte	CL:0000576	83.87	gold quality
leukocyte	CL:0000738	83.42	gold quality
placenta	UBERON:0001987	83.01	gold quality
substantia nigra	UBERON:0002038	82.89	gold quality
tonsil	UBERON:0002372	82.77	gold quality
skin of leg	UBERON:0001511	82.26	gold quality
liver	UBERON:0002107	82.18	gold quality
zone of skin	UBERON:0000014	82.06	gold quality
skin of abdomen	UBERON:0001416	81.68	gold quality
islet of Langerhans	UBERON:0000006	81.21	gold quality
bone marrow	UBERON:0002371	80.89	gold quality
sural nerve	UBERON:0015488	80.82	gold quality
Ammon’s horn	UBERON:0001954	80.79	gold quality
lower esophagus mucosa	UBERON:0035834	80.79	gold quality
adrenal tissue	UBERON:0018303	80.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.54	gold quality
cortex of kidney	UBERON:0001225	80.51	gold quality
temporal lobe	UBERON:0001871	80.40	gold quality
amygdala	UBERON:0001876	80.26	gold quality
blood	UBERON:0000178	80.12	gold quality
lymph node	UBERON:0000029	79.99	gold quality
esophagus mucosa	UBERON:0002469	79.97	gold quality
putamen	UBERON:0001874	79.88	gold quality
gall bladder	UBERON:0002110	79.74	gold quality
primary visual cortex	UBERON:0002436	79.67	gold quality
bone marrow cell	CL:0002092	79.64	gold quality
prefrontal cortex	UBERON:0000451	79.53	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	21.68
E-CURD-46	yes	12.03
E-MTAB-8498	yes	11.78
E-ANND-3	no	3.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting CLN8, 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-8485	100.00	77.57	4731
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• patients with CLN8 mutations from Italy. In these patients, the onset of epilepsy occurred between 3 and 6 years of age, with myoclonic, tonic-clonic, and atypical absence seizures. Electroencephalograms revealed focal and/or generalized abnormalities. (PMID:17129765)
• CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death. (PMID:19431184)
• a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype of neuronal ceroid lipofuscinose was described. (PMID:19807737)
• CLN8 is a candidate modifier gene for GD1. Increased expression may protect against severe GD1.It may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. (PMID:22388998)
• A missense mutation at the CLN8 gene (763C>G)has been identified in 3 consanguineous Israeli-Arab patients. The phenotype in 2 of them is milder than that of their cousin who has typical neuronal ceroid lipofuscinosis. (PMID:22964447)
• 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)
• Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis (PMID:26443629)
• This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population. (PMID:26657971)
• Whole-exome sequencing and homozygosity mapping revealed a novel homozygous CLN8 mutation, c.677T>C (p.Leu226Pro in 5 relatives from a large Turkish consanguineous family (PMID:27844444)
• CLN8 recruits lysosomal soluble proteins in the endoplasmic reticulum (ER), delivers them to the Golgi apparatus via COPII-coated vesicles, and recycles back to the ER via COPI-coated vesicles. CLN8 interacts with the lysosomal soluble proteins through its large luminal loop. The export signal of CLN8 (261VDWNF265) is localized in its cytosolic C-terminus. CLN8 deficiency results in depletion of enzymes at the lysosome. (PMID:30397314)
• the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3beta, were decreased in CLN8 disease patient fibroblasts. (PMID:30453012)
• The Neuronal Ceroid Lipofuscinoses-Linked Loss of Function CLN5 and CLN8 Variants Disrupt Normal Lysosomal Function. (PMID:30919163)
• CLN8 associates with CLN6 to form the EGRESS complex (ER-to-Golgi Relaying of Enzymes of the lySosomal System), the functional unit responsible for the recruitment of newly synthesized lysosomal enzymes in the endoplasmic reticulum and their transfer to the Golgi complex. (PMID:32597833)
• miR-3074-5p/CLN8 pathway regulates decidualization in recurrent miscarriage. (PMID:34044364)
• CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis-Literature Review and Case Report. (PMID:34201538)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cln8	ENSDARG00000075525
mus_musculus	Cln8	ENSMUSG00000026317
rattus_norvegicus	Cln8	ENSRNOG00000012565

Paralogs (5): TLCD3B (ENSG00000149926), TLCD4 (ENSG00000152078), TLCD1 (ENSG00000160606), TLCD3A (ENSG00000167695), TLCD2 (ENSG00000185561)

Protein

Protein identifiers

Protein CLN8 — Q9UBY8 (reviewed: Q9UBY8)

All UniProt accessions (5): Q9UBY8, A0A0J9YWD2, A0A0J9YYK8, A0A1B0GU79, A0A1B0GUR8

UniProt curated annotations — full annotation on UniProt →

Function. Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.

Subunit / interactions. Interacts with CLN5. Interacts with CLN3.

Subcellular location. Endoplasmic reticulum membrane. Endoplasmic reticulum-Golgi intermediate compartment membrane. Endoplasmic reticulum.

Post-translational modifications. Does not seem to be N-glycosylated.

Disease relevance. Ceroid lipofuscinosis, neuronal, 8 (CLN8) [MIM:600143] A form of neuronal ceroid lipofuscinosis with onset in childhood. 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 8 comprise mixed combinations of granular, curvilinear, and fingerprint profiles. The disease is caused by variants affecting the gene represented in this entry. Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (CLN8NE) [MIM:610003] A form of neuronal ceroid lipofuscinosis clinically characterized by epilepsy that presents between 5 and 10 years of age with frequent tonic-clonic seizures followed by progressive intellectual disability. Visual loss is not a prominent feature. Intracellular accumulation of autofluorescent material results in curvilinear and granular profiles on ultrastructural analysis. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_061764* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006634	TLC-dom	Domain
IPR050846	TLCD	Family

Pfam: PF03798

UniProt features (33 total): sequence variant 23, transmembrane region 5, chain 1, mutagenesis site 1, sequence conflict 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBY8-F1	90.47	0.83

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
283–284	localizes to the golgi complex.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 370 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_ADULT_BEHAVIOR, GOBP_ASSOCIATIVE_LEARNING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (31): phospholipid metabolic process (GO:0006644), ceramide metabolic process (GO:0006672), lipid transport (GO:0006869), mitochondrial membrane organization (GO:0007006), lysosome organization (GO:0007040), nervous system development (GO:0007399), visual perception (GO:0007601), adult walking behavior (GO:0007628), cholesterol metabolic process (GO:0008203), associative learning (GO:0008306), regulation of cell size (GO:0008361), lipid biosynthetic process (GO:0008610), somatic motor neuron differentiation (GO:0021523), protein catabolic process (GO:0030163), social behavior (GO:0035176), negative regulation of neuron apoptotic process (GO:0043524), photoreceptor cell maintenance (GO:0045494), negative regulation of proteolysis (GO:0045861), ceramide biosynthetic process (GO:0046513), musculoskeletal movement (GO:0050881), neuromuscular process controlling posture (GO:0050884), neuromuscular process controlling balance (GO:0050885), glutamate reuptake (GO:0051935), lipid homeostasis (GO:0055088), retina development in camera-type eye (GO:0060041), neurofilament cytoskeleton organization (GO:0060052), retinal rod cell apoptotic process (GO:0097473), apoptotic process (GO:0006915), adult locomotory behavior (GO:0008344), spinal cord motor neuron differentiation (GO:0021522), neuron apoptotic process (GO:0051402)

GO Molecular Function (2): ceramide binding (GO:0097001), protein binding (GO:0005515)

GO Cellular Component (7): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), membrane (GO:0016020), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), presynapse (GO:0098793)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
intracellular membrane-bounded organelle	3
lipid metabolic process	2
cellular anatomical structure	2
organophosphate metabolic process	1
sphingolipid metabolic process	1
transport	1
lipid localization	1
mitochondrion	1
mitochondrion organization	1
membrane organization	1
lytic vacuole organization	1
system development	1
sensory perception of light stimulus	1
adult locomotory behavior	1
walking behavior	1
sterol metabolic process	1
secondary alcohol metabolic process	1
learning	1
regulation of cellular component size	1
biosynthetic process	1
spinal cord motor neuron differentiation	1
macromolecule catabolic process	1
protein metabolic process	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
retina homeostasis	1
multicellular organismal process	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
multicellular organismal movement	1
neuromuscular process	1
sphingolipid binding	1
binding	1

Protein interactions and networks

STRING

1077 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLN8	CLN6	Q9NWW5	988
CLN8	CLN5	O75503	974
CLN8	PPT1	P50897	970
CLN8	CLN3	Q13286	966
CLN8	MFSD8	Q8NHS3	963
CLN8	DNAJC5	Q9H3Z4	847
CLN8	KCTD7	Q96MP8	788
CLN8	CTSD	P07339	765
CLN8	TPP1	O14773	737
CLN8	GDF1	P27539	689
CLN8	ATP13A2	Q9NQ11	685
CLN8	CTSF	Q9UBX1	630
CLN8	ARHGEF10	O15013	546
CLN8	ARSG	Q96EG1	520
CLN8	DLGAP2	Q9P1A6	491

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CLN8	FZD7	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (43): CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Proximity Label-MS), CLN8 (Two-hybrid), CLN8 (Two-hybrid), CLN8 (Proximity Label-MS), VAPA (Two-hybrid), C14orf1 (Two-hybrid), STX8 (Two-hybrid), GABARAPL2 (Two-hybrid)

ESM2 similar proteins: A1A4P6, A1A5B4, A5PK40, A6NDV4, A6NFX1, A6NGC4, A6QL84, A6QLK4, B1AWJ5, B6ID01, E1BY51, P58749, Q2TA01, Q2YDG0, Q32PG7, Q3T9M1, Q4R7X9, Q5HZE5, Q5JZQ7, Q5R6H1, Q5RBY7, Q60HE8, Q6AY05, Q6AYM9, Q6PHN7, Q6TCG5, Q6UX01, Q6UXD7, Q7RTT9, Q7Z403, Q80ZE4, Q8CE47, Q8R139, Q8TBR7, Q96FZ5, Q96HE8, Q96S97, Q9BSA9, Q9BZW5, Q9CQC4

Diamond homologs: Q5JZQ7, Q6AYM9, Q9QUK3, Q9UBY8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CLN8	“up-regulates activity”	PPP2CA	binding
CLN8	“down-regulates activity”	SET	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	29
Uncertain significance	245
Likely benign	214
Benign	11

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069263	NM_018941.4(CLN8):c.130C>T (p.Gln44Ter)	Pathogenic
1415411	NM_018941.4(CLN8):c.635G>A (p.Trp212Ter)	Pathogenic
1451868	NM_018941.4(CLN8):c.105C>G (p.Tyr35Ter)	Pathogenic
1452827	NM_018941.4(CLN8):c.543+1G>A	Pathogenic
1453381	NM_018941.4(CLN8):c.126C>A (p.Cys42Ter)	Pathogenic
1454579	NM_018941.4(CLN8):c.539T>A (p.Leu180Ter)	Pathogenic
1958204	NM_018941.4(CLN8):c.766C>T (p.Gln256Ter)	Pathogenic
1982054	NM_018941.4(CLN8):c.678_687del (p.Tyr227fs)	Pathogenic
2019654	NM_018941.4(CLN8):c.109_112dup (p.Val38fs)	Pathogenic
2066828	NM_018941.4(CLN8):c.474_477dup (p.Ala160fs)	Pathogenic
2168382	NM_018941.4(CLN8):c.159C>A (p.Tyr53Ter)	Pathogenic
241289	NM_018941.4(CLN8):c.788G>A (p.Trp263Ter)	Pathogenic
253419	GRCh37/hg19 8p23.3(chr8:1718834-1729007)x1	Pathogenic
2627378	NM_018941.4(CLN8):c.447C>A (p.Cys149Ter)	Pathogenic
2627618	NM_018941.4(CLN8):c.424dup (p.Ala142fs)	Pathogenic
2693100	NM_018941.4(CLN8):c.530G>A (p.Trp177Ter)	Pathogenic
2693723	NM_018941.4(CLN8):c.68_76del (p.Ile23_Ser25del)	Pathogenic
2747381	NM_018941.4(CLN8):c.548del (p.Gly183fs)	Pathogenic
2748417	NM_018941.4(CLN8):c.160del (p.Arg54fs)	Pathogenic
2749928	NM_018941.4(CLN8):c.1A>T (p.Met1Leu)	Pathogenic
2753375	NM_018941.4(CLN8):c.315del (p.His106fs)	Pathogenic
2757008	NM_018941.4(CLN8):c.627C>G (p.Tyr209Ter)	Pathogenic
2802	NM_018941.4(CLN8):c.70C>G (p.Arg24Gly)	Pathogenic
2803	NM_018941.4(CLN8):c.789G>C (p.Trp263Cys)	Pathogenic
2806	NM_018941.4(CLN8):c.88G>C (p.Ala30Pro)	Pathogenic
2824675	NM_018941.4(CLN8):c.377T>A (p.Leu126Ter)	Pathogenic
2843657	NM_018941.4(CLN8):c.555del (p.Glu186fs)	Pathogenic
3245411	NC_000008.10:g.(?1719221)(1719783_?)del	Pathogenic
3245412	NC_000008.10:g.(?1728396)(1728733_?)del	Pathogenic
3595450	NM_018941.4(CLN8):c.1del (p.Met1*)	Pathogenic

SpliceAI

1067 predictions. Top by Δscore:

Variant	Effect	Δscore
8:1780620:G:T	donor_gain	1.0000
8:1770927:TTTA:T	acceptor_loss	0.9900
8:1770928:TTA:T	acceptor_loss	0.9900
8:1770929:TA:T	acceptor_loss	0.9900
8:1770930:A:AC	acceptor_loss	0.9900
8:1770930:A:AG	acceptor_gain	0.9900
8:1770931:G:GG	acceptor_gain	0.9900
8:1770931:GATT:G	acceptor_gain	0.9900
8:1780244:A:AG	acceptor_gain	0.9900
8:1780244:AT:A	acceptor_gain	0.9900
8:1780245:T:G	acceptor_gain	0.9900
8:1780245:TGCA:T	acceptor_loss	0.9900
8:1780246:GCAGG:G	acceptor_loss	0.9900
8:1780247:CA:C	acceptor_loss	0.9900
8:1780248:A:AG	acceptor_gain	0.9900
8:1780248:AGGC:A	acceptor_gain	0.9900
8:1780248:AGGCG:A	acceptor_gain	0.9900
8:1780249:G:GA	acceptor_gain	0.9900
8:1780249:GGC:G	acceptor_gain	0.9900
8:1780249:GGCG:G	acceptor_gain	0.9900
8:1780249:GGCGG:G	acceptor_gain	0.9900
8:1780620:G:GT	donor_gain	0.9900
8:1780655:G:GT	donor_gain	0.9900
8:1770931:GA:G	acceptor_gain	0.9800
8:1780245:T:TA	acceptor_gain	0.9800
8:1780654:GGCA:G	donor_gain	0.9800
8:1780901:TG:T	donor_gain	0.9800
8:1780248:AG:A	acceptor_gain	0.9700
8:1780249:GG:G	acceptor_gain	0.9700
8:1780552:G:GT	donor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000032523 (8:1765817 C>T), RS1000057508 (8:1782048 G>A,C), RS1000125704 (8:1782997 C>A,G), RS1000187467 (8:1757405 C>T), RS1000213038 (8:1761453 T>C), RS1000242721 (8:1761356 G>A,T), RS1000299796 (8:1777980 A>G), RS1000467204 (8:1766040 C>G,T), RS1000504724 (8:1772596 T>C,G), RS1000534286 (8:1760606 G>A), RS1000663397 (8:1776747 G>C,T), RS1000763854 (8:1765326 C>A,G,T), RS1000797413 (8:1766211 T>C), RS1000888885 (8:1752767 A>G), RS1000895462 (8:1769436 G>A)

Disease associations

OMIM: gene MIM:607837 | disease phenotypes: MIM:600143, MIM:256730, MIM:610003, MIM:214200, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis 8	Definitive	Autosomal recessive
neuronal ceroid lipofuscinosis 8 northern epilepsy variant	Strong	Autosomal recessive
autism spectrum disorder	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Mondo (7): neuronal ceroid lipofuscinosis 8 (MONDO:0010830), neuronal ceroid lipofuscinosis (MONDO:0016295), neuronal ceroid lipofuscinosis 8 northern epilepsy variant (MONDO:0012391), neuronal ceroid lipofuscinosis 1 (MONDO:0009744), intellectual disability (MONDO:0001071), central core myopathy (MONDO:0007294), autism spectrum disorder (MONDO:0005258)

Orphanet (10): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), Neuronal ceroid lipofuscinosis (Orphanet:216), CLN8 disease (Orphanet:228354), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), OBSOLETE: Juvenile neuronal ceroid lipofuscinosis (Orphanet:79264), Northern epilepsy (Orphanet:1947), CLN1 disease (Orphanet:228329), Central core disease (Orphanet:597), Progressive myoclonic epilepsy with neuroserpin inclusion bodies (Orphanet:530298), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000550	Undetectable electroretinogram
HP:0000708	Atypical behavior
HP:0000711	Restlessness
HP:0000726	Dementia
HP:0000729	Autistic behavior
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001336	Myoclonus
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002123	Generalized myoclonic seizure
HP:0002167	Abnormal speech pattern
HP:0002312	Clumsiness
HP:0002317	Unsteady gait
HP:0002333	Motor deterioration
HP:0002353	EEG abnormality
HP:0002359	Frequent falls

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001380_1	Gaucher disease severity	1.000000e-06
GCST004765_16	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	4.000000e-08
GCST006105_3	Eye morphology	8.000000e-08
GCST006628_52	Systolic blood pressure	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007806	total cholesterol change measurement
EFO:0006335	systolic blood pressure

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300
C537952	Ceroid lipofuscinosis, neuronal 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	7
sodium arsenite	increases expression, affects cotreatment, increases abundance	3
bisphenol A	decreases methylation, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Arsenic	affects cotreatment, increases abundance, increases expression, affects methylation	2
Benzo(a)pyrene	affects methylation, increases expression	2
Endosulfan	increases expression	2
Lead	affects expression, decreases expression	2
Methyl Methanesulfonate	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
polyhexamethyleneguanidine	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	decreases methylation	1
Acetaminophen	increases expression	1
Adenine	decreases expression	1
Colchicine	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E0AD	Ubigene HeLa CLN8 KO	Cancer cell line	Female
CVCL_F0PQ	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) CLN8-/-	Embryonic stem cell	Female
CVCL_XM84	HAP1 CLN8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders