# NM_001384732.1(CPLANE1):c.3176del (p.Pro1059fs)

https://sugi.bio/variant/cplane1-p-pro1059fs

## Summary

**CPLANE1 p.Pro1059fs (c.3176del)** is classified **Pathogenic** in CPLANE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). No gnomAD frequency available for this variant; Associated with Joubert syndrome and related disorders.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2548219251 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CPLANE1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Joubert syndrome and related disorders.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019931/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPLANE1](https://sugi.bio/atlas/gene/CPLANE1/) |
| Protein change (HGVS p.) | p.Pro1059fs |
| Coding change (HGVS c.) | c.3176del |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| dbSNP | [rs2548219251](https://www.ncbi.nlm.nih.gov/snp/rs2548219251/) |
| Variant type | Deletion |
| Location | chr5:37205428-37205428 (GRCh38) |
| ClinVar | [VCV2637762](https://www.ncbi.nlm.nih.gov/clinvar/variation/2637762/) |

**All HGVS expressions:** `NC_000005.10:g.37205429del`, `NC_000005.9:g.37205531del`, `NG_032772.2:g.49001del`, `NG_032772.3:g.48948del`, `NM_001384732.1:c.3176del`, `NM_023073.4:c.3176del`, `NM_023073.4:c.3176delC`

## 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 -1.104, GERP 0.56, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.728, pLI 2.7962e-36. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 53**, 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: **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}

**CPLANE1** population constraint: LOEUF 0.728, pLI 2.7962e-36, missense-Z 2.7342; 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):

- **Joubert syndrome 17** — Definitive (AR)

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-16.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-16 |

## Associated conditions {#conditions}

[Joubert syndrome and related disorders](https://sugi.bio/atlas/disease/joubert-syndrome-and-related-disorders/).

**Reported phenotype names (ClinVar):** Joubert syndrome and related disorders.

## Similar variants {#similar}

Related CPLANE1 variant pages (same residue, condition, or type): [CPLANE1 p.Leu808fs](/variant/cplane1-p-leu808fs), [CPLANE1 p.Lys830fs](/variant/cplane1-p-lys830fs), [CPLANE1 c.7234-2_7234del](/variant/cplane1-c-7234-minus-2-7234del), [CPLANE1 p.Phe2823_Leu2824insTer](/variant/cplane1-p-phe2823-leu2824inster), [CPLANE1 p.Pro1059Leu](/variant/cplane1-p-pro1059leu), [CPLANE1 p.Pro1059=](/variant/cplane1-p-pro1059), [CPLANE1 c.7400+1G>A](/variant/cplane1-c-7400-plus-1g-a), [CPLANE1 p.Ala1783Asp](/variant/cplane1-p-ala1783asp).

### 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 2637762). 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.*