# NM_017882.3(CLN6):c.786_787dup (p.Phe263fs)

https://sugi.bio/variant/cln6-p-phe263fs

## Summary

**CLN6 p.Phe263fs (c.786_787dup)** is classified **Likely pathogenic** in CLN6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-02-16). No gnomAD frequency available for this variant; Associated with ceroid lipofuscinosis, neuronal, 6A.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1555438229 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CLN6 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ceroid lipofuscinosis, neuronal, 6A.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CLN6 is a diagnostic-grade gene on 15 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001224/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLN6](https://sugi.bio/atlas/gene/CLN6/) |
| Protein change (HGVS p.) | p.Phe263fs |
| Coding change (HGVS c.) | c.786_787dup |
| MANE Select transcript | [NM_017882](https://www.ncbi.nlm.nih.gov/nuccore/NM_017882) |
| dbSNP | [rs1555438229](https://www.ncbi.nlm.nih.gov/snp/rs1555438229/) |
| Variant type | Microsatellite |
| Location | chr15:68208288-68208289 (GRCh38) |
| ClinVar | [VCV556613](https://www.ncbi.nlm.nih.gov/clinvar/variation/556613/) |

**All HGVS expressions:** `LRG_832:g.53920CT[3]`, `LRG_832t1:c.786_787dup`, `NC_000015.10:g.68208289AG[3]`, `NC_000015.9:g.68500627AG[3]`, `NG_008764.2:g.53920CT[3]`, `NM_017882.3:c.786_787dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 9.073, GERP 1.97, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.015, pLI 8.7664e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CLN6** population constraint: LOEUF 1.015, pLI 8.7664e-06, missense-Z 0.55889. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neuronal ceroid lipofuscinosis** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.86, 62% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CLN6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CLN6's established molecular role includes lysophosphatidic acid binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** lysophosphatidic acid binding, protein homodimerization activity, sulfatide binding.

**Biological process:** ganglioside metabolic process, lysosomal lumen acidification, cholesterol metabolic process, glycosaminoglycan metabolic process, positive regulation of proteolysis.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-02-16.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2018-02-16 |

## Associated conditions {#conditions}

[ceroid lipofuscinosis, neuronal, 6A](https://sugi.bio/atlas/disease/ceroid-lipofuscinosis-neuronal-6a/).

**Reported phenotype names (ClinVar):** Ceroid lipofuscinosis, neuronal, 6A, Neuronal ceroid lipofuscinosis, late infantile, variant, Neuronal ceroid lipofuscinosis, Gypsy/Indian early juvenile variant, Neuronal ceroid lipofuscinosis 6, CLN6-Related Neuronal Ceroid-Lipofuscinosis.

## Similar variants {#similar}

Related CLN6 variant pages (same residue, condition, or type): [CLN6 p.Ser132fs](/variant/cln6-p-ser132fs), [CLN6 p.Phe263=](/variant/cln6-p-phe263), [CLN6 p.Val32fs](/variant/cln6-p-val32fs), [CLN6 p.Ser265del](/variant/cln6-p-ser265del), [CLN6 p.Ile119del](/variant/cln6-p-ile119del), [CLN6 c.486+1G>A](/variant/cln6-c-486-plus-1g-a), [CLN6 c.543-1G>A](/variant/cln6-c-543-minus-1g-a), [CLN6 c.665+1G>T](/variant/cln6-c-665-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 556613). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*