# NM_025114.4(CEP290):c.6416_6417del (p.Lys2139fs)

https://sugi.bio/variant/cep290-p-lys2139fs

## Summary

**CEP290 p.Lys2139fs (c.6416_6417del)** is classified **Likely pathogenic** in CEP290 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). Associated with focal segmental glomerulosclerosis.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CEP290 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to focal segmental glomerulosclerosis.

*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 | 77 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006517/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CEP290](https://sugi.bio/atlas/gene/CEP290/) |
| Protein change (HGVS p.) | p.Lys2139fs |
| Coding change (HGVS c.) | c.6416_6417del |
| MANE Select transcript | [NM_025114](https://www.ncbi.nlm.nih.gov/nuccore/NM_025114) |
| Variant type | Deletion |
| Location | chr12:88060935-88060936 (GRCh38) |
| ClinVar | [VCV4813872](https://www.ncbi.nlm.nih.gov/clinvar/variation/4813872/) |

**All HGVS expressions:** `LRG_694:g.86281_86282del`, `LRG_694t1:c.6416_6417del`, `NC_000012.11:g.88454716_88454717del`, `NC_000012.12:g.88060939_88060940del`, `NG_008417.2:g.86281_86282del`, `NM_025114.4:c.6416_6417del`, `NM_025114.4:c.6416_6417delAA`

## 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 7.682, GERP 2.43, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.094, pLI 1.2493e-48. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 47 of 54**, 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.

*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}

**CEP290** population constraint: LOEUF 1.094, pLI 1.2493e-48, missense-Z 0.17962; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (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):

- **CEP290-related ciliopathy** — Definitive (AR)

## Protein context {#protein}

Residue **2139** lies in a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); a UniProt-annotated variant site (in lca10); a UniProt-annotated variant site (in lca10, slsn6 and mks4); a UniProt-annotated variant site (in lca10 and slsn6); a UniProt-annotated variant site (in mks4 and jbts5); the 'self-association (with itself or n-terminus)' region.

AlphaFold model confidence (whole protein): pLDDT 60.90, 0% of residues very-high.

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

*Describes the biological roles of CEP290 (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:** CEP290's established molecular role includes identical protein binding. p.Lys2139fs falls in the self-association (with itself or n-terminus) region.


### Pathways affected {#pathways}

CEP290 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

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

**Molecular function:** identical protein binding.

**Biological process:** positive regulation of DNA-templated transcription, cilium assembly, regulation of establishment of protein localization, positive regulation of intracellular protein transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Lab, University of Sulaimaniyah | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-12 |

## Associated conditions {#conditions}

[focal segmental glomerulosclerosis](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis/).

**Reported phenotype names (ClinVar):** Focal segmental glomerulosclerosis, Glomerulosclerosis, focal, Focal sclerosis with hyalinosis.

## Same-residue context {#hotspot}

Residue **2139** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CEP290 p.Lys2139_Val2140insTer](/variant/cep290-p-lys2139-val2140inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CEP290 variant pages (same residue, condition, or type): [CEP290 p.Lys2139_Val2140insTer](/variant/cep290-p-lys2139-val2140inster), [CEP290 p.Glu842fs](/variant/cep290-p-glu842fs), [CEP290 p.Leu821fs](/variant/cep290-p-leu821fs), [CEP290 p.Lys2139Asn](/variant/cep290-p-lys2139asn), [CEP290 c.4438-3del](/variant/cep290-c-4438-minus-3del), [CEP290 p.Asn737_Leu738insTer](/variant/cep290-p-asn737-leu738inster), [CEP290 p.Ile556fs](/variant/cep290-p-ile556fs), [CEP290 p.Lys1343fs](/variant/cep290-p-lys1343fs).

### 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 4813872). 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.*