# NM_001042432.2(CLN3):c.992_993del (p.Phe331fs)

https://sugi.bio/variant/cln3-p-phe331fs

## Summary

**CLN3 p.Phe331fs (c.992_993del)** is classified **Pathogenic/Likely pathogenic** in CLN3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-29). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2046109345 · 4 submitters · 4 linked conditions · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CLN3 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Phe331fs |
| Coding change (HGVS c.) | c.992_993del |
| MANE Select transcript | [NM_001042432](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042432) |
| dbSNP | [rs2046109345](https://www.ncbi.nlm.nih.gov/snp/rs2046109345/) |
| Variant type | Deletion |
| Location | chr16:28482168-28482169 (GRCh38) |
| ClinVar | [VCV1075948](https://www.ncbi.nlm.nih.gov/clinvar/variation/1075948/) |

**All HGVS expressions:** `LRG_689:g.15134_15135del`, `LRG_689t1:c.992_993del`, `LRG_689t2:c.992_993del`, `NC_000016.10:g.28482169_28482170del`, `NC_000016.9:g.28493490_28493491del`, `NG_008654.2:g.15134_15135del`, `NM_000086.2:c.992_993del`, `NM_000086.2:c.992_993delTT`, `NM_001042432.2:c.992_993del`, `NM_001286104.2:c.920_921del`, `NM_001286105.2:c.692_693del`, `NM_001286109.2:c.758_759del`, `NM_001286110.2:c.830_831del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.31, GERP 1.5, phastCons 0.094 — weakly conserved position
- 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 exon 14 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,846 in the highest group · 1/1,461,470 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-29.

**Submitter consensus:** conflicting (2 Pathogenic, 2 Likely pathogenic).

**Submission history:** 4 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-08 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-21 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-24 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-29 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [neuronal ceroid lipofuscinosis 3](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis-3/), [neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis/), [juvenile neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/juvenile-neuronal-ceroid-lipofuscinosis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis 3, Juvenile neuronal ceroid lipofuscinosis, Batten Disease, Neuronal Ceroid Lipofuscinoses.

## Similar variants {#similar}

Related CLN3 variant pages (same residue, condition, or type): [CLN3 c.375-2del](/variant/cln3-c-375-minus-2del), [CLN3 c.461-280_677+382del](/variant/cln3-c-461-minus-280-677-plus-382del), [CLN3 c.790+1del](/variant/cln3-c-790-plus-1del), [CLN3 c.954_962+18del](/variant/cln3-c-954-962-plus-18del), [CLN3 p.Glu244fs](/variant/cln3-p-glu244fs), [CLN3 p.Glu273fs](/variant/cln3-p-glu273fs), [CLN3 p.Gly187fs](/variant/cln3-p-gly187fs), [CLN3 p.Leu214fs](/variant/cln3-p-leu214fs).

### 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 1075948). 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.*