# NM_025114.4(CEP290):c.3709C>T (p.Arg1237Cys)

https://sugi.bio/variant/cep290-p-arg1237cys

## Summary

**CEP290 p.Arg1237Cys (c.3709C>T)** is classified **Uncertain significance** in CEP290 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-22). AlphaMissense: likely benign (0.1078); Ultra-rare (popmax 0.0493%, mid); Associated with nephronophthisis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs768864296 · 7 submitters · 9 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0493%, mid)

## For patients & families {#patients}

This is a change in the CEP290 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 7 submitters, and is linked to nephronophthisis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CEP290 is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/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.Arg1237Cys |
| Coding change (HGVS c.) | c.3709C>T |
| MANE Select transcript | [NM_025114](https://www.ncbi.nlm.nih.gov/nuccore/NM_025114) |
| dbSNP | [rs768864296](https://www.ncbi.nlm.nih.gov/snp/rs768864296/) |
| Variant type | single nucleotide variant |
| Location | chr12:88089352-88089352 (GRCh38) |
| ClinVar | [VCV880644](https://www.ncbi.nlm.nih.gov/clinvar/variation/880644/) |

**All HGVS expressions:** `LRG_694:g.57865C>T`, `LRG_694t1:c.3709C>T`, `NC_000012.11:g.88483129G>A`, `NC_000012.12:g.88089352G>A`, `NG_008417.2:g.57865C>T`, `NM_025114.4:c.3709C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1078)
- REVEL 0.424 (indeterminate)
- SaProt LLR -7.727 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 9.919, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.7**. 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.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (88,049,187–88,141,307), spanning 92,120 bp. Chi-square p 0.89. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0493%** (mid) · FAF95 0.0134% · FAF99 0.00715% · 3/6,084 in the highest group · 26/1,613,742 alleles overall — ultra-rare (popmax 0.0493%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0493% | 2,028 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,615 |
| Admixed American | 0.005% | 19,993 |
| South Asian | 0.0022% | 45,540 |
| African / African-American | 0.00134% | 74,880 |
| European (non-Finnish) | 0.0011% | 90,760 |

*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 **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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-22.

**Submitter consensus:** unanimous (14/14 Uncertain significance).

**Submission history:** 14 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-17 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-27 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-14 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-22 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-19 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [Joubert syndrome 5](https://sugi.bio/atlas/disease/joubert-syndrome-5/), [Senior-Loken syndrome 6](https://sugi.bio/atlas/disease/senior-loken-syndrome-6/), [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/), [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/).

**Reported phenotype names (ClinVar):** Nephronophthisis, Senior-Loken syndrome 6, Bardet-Biedl syndrome 14, Joubert syndrome 5, Meckel syndrome, type 4, Leber congenital amaurosis 10, Leber congenital amaurosis, Joubert syndrome, Meckel-Gruber syndrome, not provided.

## Same-residue context {#hotspot}

Residue **1237** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CEP290 p.Arg1237fs](/variant/cep290-p-arg1237fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CEP290 variant pages (same residue, condition, or type): [CEP290 p.Arg1237Leu](/variant/cep290-p-arg1237leu), [CEP290 p.Arg1237His](/variant/cep290-p-arg1237his), [CEP290 p.Arg1237fs](/variant/cep290-p-arg1237fs), [CEP290 c.1189+1G>A](/variant/cep290-c-1189-plus-1g-a), [CEP290 c.1189+2T>C](/variant/cep290-c-1189-plus-2t-c), [CEP290 c.297+1G>T](/variant/cep290-c-297-plus-1g-t), [CEP290 c.2991+1655A>G](/variant/cep290-c-2991-plus-1655a-g), [CEP290 c.6271-8T>G](/variant/cep290-c-6271-minus-8t-g).

### 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 880644). 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.*