# NM_006493.4(CLN5):c.743_744dup (p.Phe249fs)

https://sugi.bio/variant/cln5-p-phe249fs

## Summary

**CLN5 p.Phe249fs (c.743_744dup)** is classified **Pathogenic** in CLN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-08). No gnomAD frequency available for this variant; Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2501155694 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CLN5 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 | [CLN5](https://sugi.bio/atlas/gene/CLN5/) |
| Protein change (HGVS p.) | p.Phe249fs |
| Coding change (HGVS c.) | c.743_744dup |
| MANE Select transcript | [NM_006493](https://www.ncbi.nlm.nih.gov/nuccore/NM_006493) |
| dbSNP | [rs2501155694](https://www.ncbi.nlm.nih.gov/snp/rs2501155694/) |
| Variant type | Microsatellite |
| Location | chr13:77000632-77000633 (GRCh38) |
| ClinVar | [VCV2825254](https://www.ncbi.nlm.nih.gov/clinvar/variation/2825254/) |

**All HGVS expressions:** `LRG_692:g.13710AG[3]`, `LRG_692t1:c.888_889AG[3]`, `NC_000013.10:g.77574768AG[3]`, `NC_000013.11:g.77000633AG[3]`, `NG_009064.1:g.13710AG[3]`, `NM_001366624.2:c.*190AG[3]`, `NM_006493.4:c.743_744dup`

## 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 4.927, GERP 2.89, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.197, pLI 3.9441e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — 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}

**CLN5** population constraint: LOEUF 1.197, pLI 3.9441e-10, missense-Z 0.27528. *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 83.05, 65% of residues very-high.

**1 experimental structure(s)** (PDB): [6R99](https://www.rcsb.org/structure/6R99).

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

*Describes the biological roles of CLN5 (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:** CLN5's established molecular role includes D-mannose binding.


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

**Molecular function:** D-mannose binding, long-chain fatty acyl-CoA hydrolase activity, bis(monoacylglycero)phosphate synthase activity.

**Biological process:** obsolete signal peptide processing, lysosomal lumen acidification, brain development, neurogenesis, retrograde transport, endosome to Golgi, positive regulation of GTP binding.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-08.

**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 | 2023-01-08 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CLN5 variant pages (same residue, condition, or type): [CLN5 p.Phe249Val](/variant/cln5-p-phe249val), [CLN5 p.Leu309fs](/variant/cln5-p-leu309fs), [CLN5 p.Phe260fs](/variant/cln5-p-phe260fs), [CLN5 p.Thr342_Tyr343insTer](/variant/cln5-p-thr342-tyr343inster), [CLN5 c.173+13GC[6]](/variant/cln5-c-173-plus-13gc-6), [CLN5 p.Leu236fs](/variant/cln5-p-leu236fs), [CLN5 p.16GA[3]](/variant/cln5-p-16ga-3), [CLN5 p.Ser356fs](/variant/cln5-p-ser356fs).

### 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 2825254). 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.*