# NM_001382391.1(CSPP1):c.1187G>C (p.Arg396Pro)

https://sugi.bio/variant/cspp1-p-arg396pro

## Summary

**CSPP1 p.Arg396Pro (c.1187G>C)** is classified **Uncertain significance** in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-26). Very rare (popmax 0.00325%, nfe); Associated with Joubert syndrome 21.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs760205035 · 1 submitter · 1 linked condition · very rare (popmax 0.00325%, nfe)

## For patients & families {#patients}

This is a change in the CSPP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Arg396Pro |
| Coding change (HGVS c.) | c.1187G>C |
| MANE Select transcript | [NM_001382391](https://www.ncbi.nlm.nih.gov/nuccore/NM_001382391) |
| dbSNP | [rs760205035](https://www.ncbi.nlm.nih.gov/snp/rs760205035/) |
| Variant type | single nucleotide variant |
| Location | chr8:67112065-67112065 (GRCh38) |
| ClinVar | [VCV1502612](https://www.ncbi.nlm.nih.gov/clinvar/variation/1502612/) |

**All HGVS expressions:** `NC_000008.10:g.68024300G>C`, `NC_000008.11:g.67112065G>C`, `NG_034100.1:g.52698G>C`, `NM_001291339.2:c.332G>C`, `NM_001363131.2:c.1106G>C`, `NM_001363132.2:c.1187G>C`, `NM_001363133.2:c.1106G>C`, `NM_001364869.1:c.1295G>C`, `NM_001364870.1:c.1115G>C`, `NM_001382391.1:c.1187G>C`, `NM_024790.7:c.1214G>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.94) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.811, GERP 1.55, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 35.0**. 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.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (67,074,253–67,195,590), spanning 121,337 bp. Chi-square p 0.15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.94**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.94**, acceptor gain **0.00**, donor gain **0.04**.
- Pangolin: Δ**0.64** (loss), gain 0.31 / loss 0.64. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00325%** (nfe) · FAF95 0.00242% · FAF99 0.00212% · 38/1,167,754 in the highest group · 39/1,597,568 alleles overall — very rare (popmax 0.00325%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00325% | 30,730 |
| African / African-American | 0.00134% | 74,352 |

*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}

Residue **396** lies in the 'disordered' region.

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. p.Arg396Pro falls in the disordered region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-26 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **396** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CSPP1 p.Arg396Gln](/variant/cspp1-p-arg396gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CSPP1 variant pages (same residue, condition, or type): [CSPP1 p.Arg396Gln](/variant/cspp1-p-arg396gln), [CSPP1 p.Arg396Ter](/variant/cspp1-p-arg396ter), [CSPP1 c.1022+1G>T](/variant/cspp1-c-1022-plus-1g-t), [CSPP1 c.1187+1G>A](/variant/cspp1-c-1187-plus-1g-a), [CSPP1 c.1497-2A>C](/variant/cspp1-c-1497-minus-2a-c), [CSPP1 c.1697+1G>T](/variant/cspp1-c-1697-plus-1g-t), [CSPP1 c.2968+1G>A](/variant/cspp1-c-2968-plus-1g-a), [CSPP1 c.2968+1G>T](/variant/cspp1-c-2968-plus-1g-t).

### 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 1502612). 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.*