CLN6

Chr 15AR

CLN6 transmembrane ER protein

Also known as: CLN4A, CLN6A, HsT18960, nclf

NCBI Gene: 54982ENSG00000128973UniProt: 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. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 6AMIM #601780
AR
Ceroid lipofuscinosis, neuronal, 6B (Kufs type)MIM #204300
AR
491
ClinVar variants
69
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— CLN6
🧬
Gene-Disease Validity (ClinGen)
neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 153 VUS of 491 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.13LOEUF
pLI 0.000
Z-score 1.23
OE 0.63 (0.37–1.13)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.01Z-score
OE missense 1.00 (0.89–1.14)
176 obs / 175.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.37–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.89–1.14)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.37
0≤1.21.6
LoF obs/exp: 8 / 12.7Missense obs/exp: 176 / 175.7Syn Z: -2.53

ClinVar Variant Classifications

491 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic37
VUS153
Likely Benign243
Benign9
Conflicting17
32
Pathogenic
37
Likely Pathogenic
153
VUS
243
Likely Benign
9
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
1
13
0
32
Likely Pathogenic
21
9
7
0
37
VUS
1
123
29
0
153
Likely Benign
0
1
92
150
243
Benign
0
0
9
0
9
Conflicting
—17
Total40134150150491

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CLN6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CLN6-related neuronal ceroid lipofuscinosis, Kufs Type, adult onset

definitive
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

CLN6-related neuronal ceroid lipofuscinosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ceroid lipofuscinosis, neuronal, 6A

MIM #601780

Molecular basis of disorder known

Autosomal recessive

Ceroid lipofuscinosis, neuronal, 6B (Kufs type)

MIM #204300

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CLN6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.
Kousi M et al.·Hum Mutat
2012Review
Adult-onset Kufs disease.
Kelly A et al.·Pract Neurol
2024
Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.
Martínez-Rubio D et al.·Int J Mol Sci
2023
Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica's experience.
Badilla-Porras R et al.·Orphanet J Rare Dis
2022
Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center.
Rus CM et al.·Orphanet J Rare Dis
2022Cohort
Human pathology in NCL.
Anderson GW et al.·Biochim Biophys Acta
2013Review
Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.
Berkovic SF et al.·Brain
2019
Single-cell and machine learning integration reveals ferroptosis-driven immune landscapes for melanoma stratification.
Wang L et al.·Front Immunol
2025
Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease).
Mitchell NL et al.·Dev Neurobiol
2023
Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy.
Specchio N et al.·Drugs
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Neuronal Ceroid LipofuscinosisBatten DiseaseCLN1 Disease

Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database

RECRUITING
NCT04613089Universitätsklinikum Hamburg-EppendorfStarted 2020-04-08
Natural History
Batten DiseaseCLN6

Natural History of Neuronal Ceroid Lipofuscinosis, Batten's CLN6 Diseae

ACTIVE NOT RECRUITING
NCT03285425Emily de los ReyesStarted 2017-01
Natural history
CLN6Batten Disease

Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer

ACTIVE NOT RECRUITING
NCT04273243Emily de los ReyesStarted 2020-01-24
AT-GTX-501

External Resources

Links to major genomics databases and tools