# NM_001382391.1(CSPP1):c.1507del (p.Leu503fs)

https://sugi.bio/variant/cspp1-p-leu503fs

## Summary

**CSPP1 p.Leu503fs (c.1507del)** is classified **Pathogenic** in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). Associated with Joubert syndrome 21.

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

## For patients & families {#patients}

This is a change in the CSPP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Joubert syndrome 21.

*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/0015997/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CSPP1](https://sugi.bio/atlas/gene/CSPP1/) |
| Protein change (HGVS p.) | p.Leu503fs |
| Coding change (HGVS c.) | c.1507del |
| MANE Select transcript | [NM_001382391](https://www.ncbi.nlm.nih.gov/nuccore/NM_001382391) |
| Variant type | Deletion |
| Location | chr8:67118258-67118258 (GRCh38) |
| ClinVar | [VCV4688585](https://www.ncbi.nlm.nih.gov/clinvar/variation/4688585/) |

**All HGVS expressions:** `NC_000008.10:g.68030493del`, `NC_000008.11:g.67118258del`, `NG_034100.1:g.58891del`, `NM_001291339.2:c.610del`, `NM_001363131.2:c.1426del`, `NM_001363132.2:c.1465del`, `NM_001363133.2:c.1384del`, `NM_001364869.1:c.1573del`, `NM_001364870.1:c.1393del`, `NM_001382391.1:c.1507del`, `NM_001438330.1:c.1492del`, `NM_001438331.1:c.1492del`, `NM_001438332.1:c.961del`, `NM_024790.7:c.1492del`

## 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 1.601, GERP 0.456, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.876, pLI 1.8241e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 31**, 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}

**CSPP1** population constraint: LOEUF 0.876, pLI 1.8241e-09, missense-Z 0.73622; 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 21** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 57.34, 8% of residues very-high.

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

*Describes the biological roles of CSPP1 (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:** CSPP1's established molecular role includes identical protein binding.


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

**Molecular function:** identical protein binding.

**Biological process:** positive regulation of cytokinesis, positive regulation of cell division.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-04.

**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 | 2025-12-04 |

## Associated conditions {#conditions}

[Joubert syndrome 21](https://sugi.bio/atlas/disease/joubert-syndrome-21/).

**Reported phenotype names (ClinVar):** Joubert syndrome 21.

## Similar variants {#similar}

Related CSPP1 variant pages (same residue, condition, or type): [CSPP1 c.-54_-51del](/variant/cspp1-c-minus-54-minus-51del), [CSPP1 p.Asn908fs](/variant/cspp1-p-asn908fs), [CSPP1 p.Gln753fs](/variant/cspp1-p-gln753fs), [CSPP1 p.Glu11fs](/variant/cspp1-p-glu11fs), [CSPP1 p.Glu755fs](/variant/cspp1-p-glu755fs), [CSPP1 p.Glu89fs](/variant/cspp1-p-glu89fs), [CSPP1 p.His85fs](/variant/cspp1-p-his85fs), [CSPP1 p.Ile841fs](/variant/cspp1-p-ile841fs).

### 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 4688585). 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.*