# NM_025114.4(CEP290):c.3708dup (p.Arg1237fs)

https://sugi.bio/variant/cep290-p-arg1237fs

## Summary

**CEP290 p.Arg1237fs (c.3708dup)** is classified **Pathogenic/Likely pathogenic** in CEP290 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-12). Very rare (popmax 0.0011%, sas); Associated with CEP290-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs758991387 · 9 submitters · 11 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CEP290 gene that is considered likely disease-causing, submitted by 9 submitters, and is linked to CEP290-related disorder.

*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 | [CEP290](https://sugi.bio/atlas/gene/CEP290/) |
| Protein change (HGVS p.) | p.Arg1237fs |
| Coding change (HGVS c.) | c.3708dup |
| MANE Select transcript | [NM_025114](https://www.ncbi.nlm.nih.gov/nuccore/NM_025114) |
| dbSNP | [rs758991387](https://www.ncbi.nlm.nih.gov/snp/rs758991387/) |
| Variant type | Duplication |
| Location | chr12:88089352-88089353 (GRCh38) |
| ClinVar | [VCV1071036](https://www.ncbi.nlm.nih.gov/clinvar/variation/1071036/) |

**All HGVS expressions:** `LRG_694:g.57864dup`, `LRG_694t1:c.3708dup`, `NC_000012.11:g.88483130dup`, `NC_000012.12:g.88089353dup`, `NG_008417.2:g.57864dup`, `NM_025114.3:c.3708dup`, `NM_025114.4:c.3708dup`, `NM_025114.4:c.3708dupG`

## 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 9.919, 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 31 of 54**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- 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 (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000429% · FAF99 0.000313% · 1/91,080 in the highest group · 12/1,613,742 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,460 |
| South Asian (grpmax) | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000848% | 117,988 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **1237** 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).

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.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-12.

**Submitter consensus:** conflicting (5 Likely pathogenic, 3 Pathogenic, 1 not provided).

**Submission history:** 7 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-06 |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-08-19 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-01 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-20 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-12 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-04-22 |

## Associated conditions {#conditions}

[CEP290-related disorder](https://sugi.bio/atlas/disease/cep290-related-disorder/), [Joubert syndrome 5](https://sugi.bio/atlas/disease/joubert-syndrome-5/), [Meckel syndrome, type 4](https://sugi.bio/atlas/disease/meckel-syndrome-type-4/), [Leber congenital amaurosis 10](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-10/), [Bardet-Biedl syndrome 14](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-14/), [Senior-Loken syndrome](https://sugi.bio/atlas/disease/senior-loken-syndrome/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/), [Meckel syndrome](https://sugi.bio/atlas/disease/meckel-syndrome/), [Leber congenital amaurosis](https://sugi.bio/atlas/disease/leber-congenital-amaurosis/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [CEP290-related ciliopathy](https://sugi.bio/atlas/disease/cep290-related-ciliopathy/).

**Reported phenotype names (ClinVar):** CEP290-related disorder, Joubert syndrome, Meckel-Gruber syndrome, Nephronophthisis, Meckel syndrome, type 4, Joubert syndrome 5, Leber congenital amaurosis 10, Renal dysplasia and retinal aplasia, Bardet-Biedl syndrome 14, Leber congenital amaurosis.

## Similar variants {#similar}

Related CEP290 variant pages (same residue, condition, or type): [CEP290 p.Arg1237Cys](/variant/cep290-p-arg1237cys), [CEP290 p.Arg1237Leu](/variant/cep290-p-arg1237leu), [CEP290 p.Arg1237His](/variant/cep290-p-arg1237his), [CEP290 p.Asn1775fs](/variant/cep290-p-asn1775fs), [CEP290 p.Asn85fs](/variant/cep290-p-asn85fs), [CEP290 p.Asp450fs](/variant/cep290-p-asp450fs), [CEP290 p.Leu1155fs](/variant/cep290-p-leu1155fs), [CEP290 p.Lys1042Ter](/variant/cep290-p-lys1042ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1071036). 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.*