CLN6

Summary

CLN6 (CLN6 transmembrane ER protein, HGNC:2077) is a protein-coding gene on chromosome 15q23, encoding Ceroid-lipofuscinosis neuronal protein 6 (Q9NWW5).

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 54982 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 829 total — 58 pathogenic, 48 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• MANE Select transcript: NM_017882

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2077
Approved symbol	CLN6
Name	CLN6 transmembrane ER protein
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20561, HsT18960, nclf
Ensembl gene	ENSG00000128973
Ensembl biotype	protein_coding
OMIM	606725
Entrez	54982

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 13 protein_coding, 9 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000249806, ENST00000538696, ENST00000563917, ENST00000564752, ENST00000564846, ENST00000565471, ENST00000566347, ENST00000567060, ENST00000569336, ENST00000635747, ENST00000635754, ENST00000636020, ENST00000636212, ENST00000636314, ENST00000636674, ENST00000636876, ENST00000636964, ENST00000637223, ENST00000637329, ENST00000637450, ENST00000637494, ENST00000637667, ENST00000637823, ENST00000638076, ENST00000638144, ENST00000856075, ENST00000856076, ENST00000913237, ENST00000913238, ENST00000971147

RefSeq mRNA: 2 — MANE Select: NM_017882 NM_001411068, NM_017882

CCDS: CCDS10227, CCDS92032

Canonical transcript exons

ENST00000249806 — 7 exons

Exon	Start	End
ENSE00000695882	68211675	68211863
ENSE00001902141	68206992	68208410
ENSE00003576561	68209637	68209759
ENSE00003581490	68211263	68211318
ENSE00003608887	68214290	68214388
ENSE00003691279	68218536	68218650
ENSE00003792380	68229502	68229728

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 90.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.2031 / max 267.5963, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150635	37.1813	1811
150634	1.0898	652
150633	0.6257	386
150630	0.3063	158

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	90.93	gold quality
leukocyte	CL:0000738	90.67	gold quality
bone marrow	UBERON:0002371	89.76	gold quality
bone element	UBERON:0001474	89.75	gold quality
mucosa of transverse colon	UBERON:0004991	89.21	gold quality
bone marrow cell	CL:0002092	89.09	gold quality
rectum	UBERON:0001052	88.83	gold quality
cortex of kidney	UBERON:0001225	88.71	gold quality
placenta	UBERON:0001987	87.55	gold quality
adult mammalian kidney	UBERON:0000082	87.50	gold quality
islet of Langerhans	UBERON:0000006	87.30	gold quality
blood	UBERON:0000178	87.28	gold quality
vermiform appendix	UBERON:0001154	87.24	gold quality
kidney	UBERON:0002113	87.13	gold quality
spleen	UBERON:0002106	86.89	gold quality
pancreas	UBERON:0001264	86.86	gold quality
left adrenal gland	UBERON:0001234	86.65	gold quality
right adrenal gland	UBERON:0001233	86.62	gold quality
lymph node	UBERON:0000029	86.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.57	gold quality
body of pancreas	UBERON:0001150	86.56	gold quality
metanephros cortex	UBERON:0010533	86.54	gold quality
granulocyte	CL:0000094	86.42	gold quality
right lobe of liver	UBERON:0001114	86.33	gold quality
right adrenal gland cortex	UBERON:0035827	86.28	gold quality
left adrenal gland cortex	UBERON:0035825	86.26	gold quality
gastrocnemius	UBERON:0001388	86.14	gold quality
duodenum	UBERON:0002114	86.11	gold quality
lower esophagus mucosa	UBERON:0035834	85.92	gold quality
adrenal gland	UBERON:0002369	85.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	14.08
E-ANND-3	yes	4.81
E-MTAB-7303	no	79.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting CLN6, 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-185-3P	99.95	67.01	1743
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-3132	97.96	67.91	711

Literature-anchored findings (GeneRIF, showing 28)

• gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein (PMID:11727201)
• novel approximately 36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes neuronal ceroid lipofuscinosis in mouse and man (PMID:11791207)
• Eight novel mutations identified in CLN6 in 26 families with late infantile neuronal ceroid lipofuscinosis. (PMID:12815591)
• ER-resident CLN6 protein lead to lysosomal dysfunctions, which may result in lysosomal accumulation of storage material (PMID:15010453)
• CLN6 is an ER resident protein, the activity of which, despite this location, must contribute to lysosomal function. (PMID:15265688)
• These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish variant late-infantile neuronal ceroid lipofuscinosis patients. (PMID:15996215)
• Cholesterol accumulation in lysosomes suggests a homeostasis block as a result of CLN6p deficiency, while dysfunctional endosomal/lysosomal vesicles may act as one of the triggers for apoptosis and cell death. (PMID:16857350)
• CLN6 maintains its endoplasmic reticulum localization by expressing retention signals present in both the N-terminal cytosolic domain and in the carboxy-proximal transmembrane domains 6 and 7. (PMID:17453415)
• knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6(G123D) and Cln6(M241T) polypeptides. (PMID:18811591)
• 11 mutations in patients with neuronal ceroid lipofuscinoses, eight of which are novel, were detected in CLN6, all predicting a direct impairing of the putative gene function. (PMID:19135028)
• three families with CLN6-associated variant late infantile neuronal ceroid lipofuscinosis from Saudi Arabia are described; one had a novel mutation in the CLN6 gene (PMID:19520283)
• Expression studies of three mutations found in CLN6 patients predicted to affect transmembrane domain 3, cytoplasmic loop 2 or result in a truncated membrane protein respectively, is reported. (PMID:20020536)
• CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival. (PMID:21359198)
• Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy. (PMID:21549341)
• our results add CLN6 to the genetic mutations causing teenage-onset progressive myoclonus epilepsy (PMID:22883287)
• The study describes the first report in the North of Morocco of the CLN6 p.I154del mutation in 3 patients belonging to a large consanguineous family. (PMID:23180398)
• study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of Neuronal ceroid lipofuscinoses. (PMID:24581221)
• describe the spectrum of clinical and neurophysiologic features associated with mutations of CLN6. (PMID:26115733)
• The CLN6 is not only a molecular entity of the anti-aggregate activity conferred by the ER manipulation using TMalphaBC, but also serves as a potential target of therapeutic interventions. (PMID:28476624)
• Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment (PMID:30528883)
• Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. (PMID:30561534)
• compound heterozygous mutations of CLN6:c.486+2T>C and c.486+4A>T are possibly the genetic causes of the autosomal recessive neuronal ceroid lipofuscinoses (PMID:31901039)
• Implications of graded reductions in CLN6’s anti-aggregate activity for the development of the neuronal ceroid lipofuscinoses. (PMID:32171521)
• The CLN6 protein associates with the CLN8 protein to form the EGRESS complex (ER-to-Golgi Relaying of Enzymes of the lySosomal System), which mediates ER exit and Golgi transfer of newly synthesized lysosomal enzymes. The second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes. Loss-of-function mutations in CLN6 affect enzyme trafficking and result in lower levels of enzymes at the lysosome. (PMID:32597833)
• CLN6’s luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses. (PMID:34380921)
• p.Asn77Lys homozygous CLN6 mutation in two unrelated Japanese patients with Kufs disease, an adult onset neuronal ceroid lipofuscinosis. (PMID:34597687)
• Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica’s experience. (PMID:35012600)
• Whole exome sequencing identifies variable expressivity of CLN6 variants in Progressive myoclonic epilepsy affected families. (PMID:38382230)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cln6b	ENSDARG00000090002
mus_musculus	Cln6	ENSMUSG00000032245
rattus_norvegicus	Cln6	ENSRNOG00000007164

Protein

Protein identifiers

Ceroid-lipofuscinosis neuronal protein 6 — Q9NWW5 (reviewed: Q9NWW5)

All UniProt accessions (16): Q9NWW5, A0A024R601, A0A0S2Z5D0, A0A1B0GTD3, A0A1B0GTU6, A0A1B0GTV3, A0A1B0GU39, A0A1B0GU90, A0A1B0GUD2, A0A1B0GUQ7, A0A1B0GUY3, A0A1B0GVR8, H3BNF1, H3BTY4, H3BUT1, H3BUV4

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with CRMP2. Interacts with CLN5. Interacts with CLN3.

Subcellular location. Endoplasmic reticulum membrane. Endoplasmic reticulum.

Disease relevance. Ceroid lipofuscinosis, neuronal, 6 (CLN6) [MIM:601780] An autosomal recessive 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 6 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, 4A (Kufs type), autosomal recessive (CLN4A) [MIM:204300] An adult-onset 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. CLN4A has no visual involvement and is characterized by progressive myoclonic epilepsy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NWW5-1	1	yes
Q9NWW5-2	2

RefSeq proteins (2): NP_001397997, NP_060352* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029255	CLN6	Family

Pfam: PF15156

UniProt features (42 total): sequence variant 32, transmembrane region 7, chain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWW5-F1	85.86	0.62

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 209 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_BEHAVIOR, SEMBA_FHIT_TARGETS_DN, GOBP_VACUOLE_ORGANIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_VACUOLAR_ACIDIFICATION, GOBP_AMINOGLYCAN_METABOLIC_PROCESS, LIAO_METASTASIS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_PH

GO Biological Process (9): ganglioside metabolic process (GO:0001573), lysosome organization (GO:0007040), lysosomal lumen acidification (GO:0007042), visual perception (GO:0007601), cholesterol metabolic process (GO:0008203), protein catabolic process (GO:0030163), glycosaminoglycan metabolic process (GO:0030203), locomotion involved in locomotory behavior (GO:0031987), positive regulation of proteolysis (GO:0045862)

GO Molecular Function (4): lysophosphatidic acid binding (GO:0035727), protein homodimerization activity (GO:0042803), sulfatide binding (GO:0120146), protein binding (GO:0005515)

GO Cellular Component (7): nucleolus (GO:0005730), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), membrane raft (GO:0045121)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ceramide metabolic process	1
glycosphingolipid metabolic process	1
lytic vacuole organization	1
vacuolar acidification	1
sensory perception of light stimulus	1
sterol metabolic process	1
secondary alcohol metabolic process	1
macromolecule catabolic process	1
protein metabolic process	1
aminoglycan metabolic process	1
locomotory behavior	1
locomotion	1
proteolysis	1
regulation of proteolysis	1
positive regulation of protein metabolic process	1
phospholipid binding	1
anion binding	1
carbohydrate derivative binding	1
identical protein binding	1
protein dimerization activity	1
glycolipid binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
endosome	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
membrane microdomain	1

Protein interactions and networks

STRING

858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLN6	CLN8	Q9UBY8	988
CLN6	CLN5	O75503	982
CLN6	CLN3	Q13286	979
CLN6	PPT1	P50897	977
CLN6	MFSD8	Q8NHS3	948
CLN6	DNAJC5	Q9H3Z4	862
CLN6	KCTD7	Q96MP8	798
CLN6	TPP1	O14773	773
CLN6	CTSD	P07339	766
CLN6	PPT2	Q9UMR5	709
CLN6	CTSF	Q9UBX1	686
CLN6	ATP13A2	Q9NQ11	679
CLN6	SGSH	P51688	608
CLN6	ARSG	Q96EG1	593
CLN6	KLC4	Q9NSK0	589

IntAct

134 interactions, top by confidence:

A	B	Type	Score
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
STX1A	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CLN6	TEX264	psi-mi:“MI:0915”(physical association)	0.560
TMPRSS2	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CLEC10A	CLN6	psi-mi:“MI:0915”(physical association)	0.560
RIC3	CLN6	psi-mi:“MI:0915”(physical association)	0.560
SLC22A23	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CYBC1	CLN6	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	CLN6	psi-mi:“MI:0915”(physical association)	0.560
EVI2B	CLN6	psi-mi:“MI:0915”(physical association)	0.560
EBAG9	CLN6	psi-mi:“MI:0915”(physical association)	0.560
SLC30A4	CLN6	psi-mi:“MI:0915”(physical association)	0.560
GORAB	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CISD2	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CPLX4	CLN6	psi-mi:“MI:0915”(physical association)	0.560
FNDC9	CLN6	psi-mi:“MI:0915”(physical association)	0.560
TMEM237	CLN6	psi-mi:“MI:0915”(physical association)	0.560
GJA8	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CD79A	CLN6	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	CLN6	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	CLN6	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL3	CLN6	psi-mi:“MI:0915”(physical association)	0.560
LIME1	CLN6	psi-mi:“MI:0915”(physical association)	0.560
LRRC25	CLN6	psi-mi:“MI:0915”(physical association)	0.560
TMEM139	CLN6	psi-mi:“MI:0915”(physical association)	0.560
EPHB2	CLN6	psi-mi:“MI:0915”(physical association)	0.560
WWP2	CLN6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (115): CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-RNA), CLN6 (Two-hybrid), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CRYAB (Affinity Capture-Western), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Affinity Capture-MS), CLN6 (Two-hybrid), CLN6 (Two-hybrid)

ESM2 similar proteins: A2AF53, A4FV75, A4K2N5, A4K2W1, A5A6S6, A6QL84, A6ZIQ8, A9JRA0, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O60337, P58749, Q08DE2, Q108U3, Q2TBU2, Q3SYY9, Q3TMP8, Q4R5E3, Q58DA4, Q5BJW3, Q5JZQ8, Q5R8H8, Q5R9W1, Q5RBJ7, Q5RFE0, Q5ZII3, Q62302, Q6UWH6, Q6ZQ89, Q78S06, Q7SYC7, Q7ZUA6, Q86W33, Q8CIF6, Q8K0B2, Q8N2H4, Q8NBJ9, Q8NFB2

Diamond homologs: Q5JZQ8, Q9NWW5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	48
Uncertain significance	244
Likely benign	355
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068527	NM_017882.3(CLN6):c.583_596del (p.Gly195fs)	Pathogenic
1071216	NM_017882.3(CLN6):c.121del (p.Ala41fs)	Pathogenic
1075854	NM_017882.3(CLN6):c.196dup (p.Met66fs)	Pathogenic
1180629	NM_017882.3(CLN6):c.396dup (p.Val133fs)	Pathogenic
1184729	NM_017882.3(CLN6):c.218_220dup (p.Trp73dup)	Pathogenic
1322096	NM_017882.3(CLN6):c.144G>A (p.Trp48Ter)	Pathogenic
1326899	NM_017882.3(CLN6):c.350T>G (p.Ile117Ser)	Pathogenic
1400355	NM_017882.3(CLN6):c.149_150insATCCT (p.Tyr50Ter)	Pathogenic
1451380	NM_017882.3(CLN6):c.655del (p.Leu219fs)	Pathogenic
1456018	NM_017882.3(CLN6):c.289_290dup (p.Leu97fs)	Pathogenic
1722846	NM_017882.3(CLN6):c.1_11del (p.Met1fs)	Pathogenic
2028846	NM_017882.3(CLN6):c.266_267insAATCCTA (p.Tyr89Ter)	Pathogenic
2033894	NM_017882.3(CLN6):c.546del (p.Trp181_Tyr182insTer)	Pathogenic
205170	NM_017882.3(CLN6):c.486+2T>C	Pathogenic
2065167	NM_017882.3(CLN6):c.407del (p.Arg136fs)	Pathogenic
2087279	NM_017882.3(CLN6):c.219G>A (p.Trp73Ter)	Pathogenic
2103197	NM_017882.3(CLN6):c.510C>A (p.Tyr170Ter)	Pathogenic
2129163	NM_017882.3(CLN6):c.739del (p.His247fs)	Pathogenic
2426366	NC_000015.9:g.(?68499209)(68500605_?)del	Pathogenic
2627623	NM_017882.3(CLN6):c.278C>A (p.Thr93Lys)	Pathogenic
265681	NM_017882.3(CLN6):c.198+1G>A	Pathogenic
2694325	NM_017882.3(CLN6):c.342C>A (p.Tyr114Ter)	Pathogenic
2736229	NM_017882.3(CLN6):c.426C>G (p.Tyr142Ter)	Pathogenic
2738552	NM_017882.3(CLN6):c.456del (p.Ile153fs)	Pathogenic
2771270	NM_017882.3(CLN6):c.872dup (p.Val293fs)	Pathogenic
2775560	NM_017882.3(CLN6):c.247dup (p.Asp83fs)	Pathogenic
2822545	NM_017882.3(CLN6):c.1A>C (p.Met1Leu)	Pathogenic
2830675	NM_017882.3(CLN6):c.180dup (p.Gly61fs)	Pathogenic
2837514	NM_017882.3(CLN6):c.601A>T (p.Lys201Ter)	Pathogenic
2852290	NM_017882.3(CLN6):c.183del (p.Arg62fs)	Pathogenic

SpliceAI

1458 predictions. Top by Δscore:

Variant	Effect	Δscore
15:68208142:AGTG:A	donor_gain	1.0000
15:68208214:T:TA	donor_gain	1.0000
15:68208409:ACC:A	acceptor_loss	1.0000
15:68214284:CAGTA:C	donor_loss	1.0000
15:68214285:AGTAC:A	donor_loss	1.0000
15:68214286:GTAC:G	donor_loss	1.0000
15:68214287:TA:T	donor_loss	1.0000
15:68214289:C:CT	donor_loss	1.0000
15:68214385:CCAG:C	acceptor_gain	1.0000
15:68214386:CAGC:C	acceptor_gain	1.0000
15:68208211:T:TA	donor_gain	0.9900
15:68208406:GGTAC:G	acceptor_gain	0.9900
15:68208408:TAC:T	acceptor_gain	0.9900
15:68208409:AC:A	acceptor_gain	0.9900
15:68208410:CC:C	acceptor_gain	0.9900
15:68208411:C:CA	acceptor_loss	0.9900
15:68208411:C:CC	acceptor_gain	0.9900
15:68208412:T:C	acceptor_loss	0.9900
15:68209629:CCACT:C	donor_loss	0.9900
15:68209630:CACTC:C	donor_loss	0.9900
15:68209631:ACTCA:A	donor_loss	0.9900
15:68209632:CTCAC:C	donor_loss	0.9900
15:68209633:T:TA	donor_loss	0.9900
15:68209634:CACCA:C	donor_loss	0.9900
15:68209635:A:T	donor_loss	0.9900
15:68209636:C:A	donor_loss	0.9900
15:68209758:ACC:A	acceptor_loss	0.9900
15:68209759:CCT:C	acceptor_loss	0.9900
15:68209759:CCTG:C	acceptor_loss	0.9900
15:68209760:C:CA	acceptor_loss	0.9900

AlphaMissense

2045 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:68211786:G:C	S125R	0.999
15:68211786:G:T	S125R	0.999
15:68211788:T:G	S125R	0.999
15:68211751:A:G	L137P	0.998
15:68211794:C:G	G123R	0.998
15:68214340:C:G	D83H	0.998
15:68218592:A:G	W48R	0.998
15:68218592:A:T	W48R	0.998
15:68211287:T:A	D173V	0.997
15:68211708:G:C	N151K	0.997
15:68211708:G:T	N151K	0.997
15:68211763:A:T	V133D	0.997
15:68211778:A:G	L128P	0.997
15:68218558:T:A	D59V	0.997
15:68211287:T:G	D173A	0.996
15:68211754:C:G	R136P	0.996
15:68211766:G:A	S132F	0.996
15:68211767:A:G	S132P	0.996
15:68211862:A:G	L100P	0.996
15:68214339:T:A	D83V	0.996
15:68218559:C:G	D59H	0.996
15:68218568:A:G	W56R	0.996
15:68218568:A:T	W56R	0.996
15:68208250:A:G	W276R	0.995
15:68208250:A:T	W276R	0.995
15:68209651:A:C	S217R	0.995
15:68209651:A:T	S217R	0.995
15:68209653:T:G	S217R	0.995
15:68211302:A:G	L168P	0.995
15:68211755:G:T	R136S	0.995

dbSNP variants (sampled 300 via entrez): RS1000098452 (15:68210272 C>T), RS1000145597 (15:68258645 T>C), RS1000262275 (15:68258161 A>G), RS1000355709 (15:68222819 A>G), RS1000379165 (15:68226626 C>T), RS1000388084 (15:68222576 A>G,T), RS1000456474 (15:68253143 T>A), RS1000482168 (15:68259077 T>C,G), RS1000512991 (15:68258832 A>G,T), RS1000546407 (15:68214535 G>C), RS1000623854 (15:68245043 A>AAAG), RS1000692578 (15:68221029 T>A), RS1000892469 (15:68231270 G>A,C), RS1000917073 (15:68232623 A>G), RS1000940529 (15:68210876 A>C)

Disease associations

OMIM: gene MIM:606725 | disease phenotypes: MIM:256730, MIM:204300, MIM:601780, MIM:108600, MIM:218000, MIM:219700

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	Autosomal recessive
ceroid lipofuscinosis, neuronal, 6B (Kufs type)	Definitive	Autosomal recessive
ceroid lipofuscinosis, neuronal, 6A	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 (10): neuronal ceroid lipofuscinosis (MONDO:0016295), ceroid lipofuscinosis, neuronal, 6B (Kufs type) (MONDO:0008768), ceroid lipofuscinosis, neuronal, 6A (MONDO:0011144), spastic ataxia (MONDO:0017845), neurodevelopmental disorder (MONDO:0700092), congenital nervous system disorder (MONDO:0002320), agenesis of the corpus callosum with peripheral neuropathy (MONDO:0000902), adult neuronal ceroid lipofuscinosis (MONDO:0019260), cystic fibrosis (MONDO:0009061), retinal disorder (MONDO:0005283)

Orphanet (10): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Adult CLN6 disease (Orphanet:700477), OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN6 disease (Orphanet:228363), Spastic ataxia (Orphanet:316226), Corpus callosum agenesis-neuronopathy syndrome (Orphanet:1496), OBSOLETE: CLN4A disease (Orphanet:228340), OBSOLETE: Adult neuronal ceroid lipofuscinosis (Orphanet:79262), Cystic fibrosis (Orphanet:586)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000529	Progressive visual loss
HP:0000546	Retinal degeneration
HP:0000716	Depression
HP:0000726	Dementia
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001268	Mental deterioration
HP:0001311	Abnormal nervous system electrophysiology
HP:0001336	Myoclonus
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002333	Motor deterioration
HP:0002352	Leukoencephalopathy
HP:0002367	Visual hallucination
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:0003581	Adult onset
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003657	Vascular granular osmiophilic material deposition
HP:0007359	Focal-onset seizure
HP:0008765	Auditory hallucination
HP:0011462	Young adult onset
HP:0031475	Status epilepticus without prominent motor symptoms

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001850_6	Major depressive disorder	3.000000e-07
GCST005042_16	Restless legs syndrome	5.000000e-69

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D065886	Neurodevelopmental Disorders	F03.625
D012164	Retinal Diseases	C11.768
C566627	Ceroid Lipofuscinosis, Neuronal, 6 (supp.)
C536446	Corpus callosum agenesis neuronopathy (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066382 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	affects cotreatment, increases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
nickel acetate	affects expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
Bortezomib	decreases expression	1
Citrinin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Lead	increases expression	1
Methapyrilene	increases methylation	1
Oxygen	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651127	Binding	Binding affinity to human CLN6 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

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_D5FC	HeLa::TMEM192-3xHA CLN6 partial KO	Cancer cell line	Female
CVCL_F0PP	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) CLN6-/-	Embryonic stem cell	Female
CVCL_SJ29	HAP1 CLN6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

213 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,
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
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
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
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
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
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies
NCT03285425	Not specified	ACTIVE_NOT_RECRUITING	Natural History of Neuronal Ceroid Lipofuscinosis, Batten’s CLN6 Diseae
NCT04273243	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder