# NM_001042432.2(CLN3):c.1246_1247dup (p.Asp416fs)

https://sugi.bio/variant/cln3-p-asp416fs

## Summary

**CLN3 p.Asp416fs (c.1246_1247dup)** is classified **Pathogenic** in CLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-03). No gnomAD frequency available for this variant; Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2506414595 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CLN3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to neuronal ceroid lipofuscinosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010739/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLN3](https://sugi.bio/atlas/gene/CLN3/) |
| Protein change (HGVS p.) | p.Asp416fs |
| Coding change (HGVS c.) | c.1246_1247dup |
| MANE Select transcript | [NM_001042432](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042432) |
| dbSNP | [rs2506414595](https://www.ncbi.nlm.nih.gov/snp/rs2506414595/) |
| Variant type | Duplication |
| Location | chr16:28477585-28477586 (GRCh38) |
| ClinVar | [VCV2729506](https://www.ncbi.nlm.nih.gov/clinvar/variation/2729506/) |

**All HGVS expressions:** `LRG_689:g.19716_19717dup`, `LRG_689t1:c.1246_1247dup`, `LRG_689t2:c.1246_1247dup`, `NC_000016.10:g.28477586_28477587dup`, `NC_000016.9:g.28488907_28488908dup`, `NG_008654.2:g.19716_19717dup`, `NM_000086.2:c.1246_1247dup`, `NM_001042432.2:c.1246_1247dup`, `NM_001286104.2:c.1174_1175dup`, `NM_001286105.2:c.946_947dup`, `NM_001286109.2:c.1012_1013dup`, `NM_001286110.2:c.1084_1085dup`

## 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 3.178, GERP 1.2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.022, pLI 5.3225e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (16 of 16)** — 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 duplication 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}

**CLN3** population constraint: LOEUF 1.022, pLI 5.3225e-14, missense-Z 0.97718; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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 81.81, 55% of residues very-high.

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

*Describes the biological roles of CLN3 (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:** CLN3's established molecular role includes glycolipid binding.


### Pathways affected {#pathways}

CLN3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid transport](https://reactome.org/content/detail/R-HSA-9845576) | curated |

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

**Molecular function:** glycolipid binding, sulfatide binding.

**Biological process:** receptor-mediated endocytosis, lysosomal lumen acidification, regulation of fibroblast migration, lysosomal lumen pH elevation, amyloid precursor protein catabolic process, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-03.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis, Neuronal Ceroid Lipofuscinoses.

## Same-residue context {#hotspot}

Residue **416** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CLN3 p.Asp416Gly](/variant/cln3-p-asp416gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CLN3 variant pages (same residue, condition, or type): [CLN3 p.Asp416Gly](/variant/cln3-p-asp416gly), [CLN3 p.Asp416=](/variant/cln3-p-asp416), [CLN3 p.Ala191fs](/variant/cln3-p-ala191fs), [CLN3 p.Arg127fs](/variant/cln3-p-arg127fs), [CLN3 p.Ser208fs](/variant/cln3-p-ser208fs), [CLN3 p.Val374fs](/variant/cln3-p-val374fs), [CLN3 c.375-19_375-4dup](/variant/cln3-c-375-minus-19-375-minus-4dup), [CLN3 p.Gly201fs](/variant/cln3-p-gly201fs).

### 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 2729506). 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.*