# NM_001382391.1(CSPP1):c.3493C>T (p.Pro1165Ser)

https://sugi.bio/variant/cspp1-p-pro1165ser

## Summary

**CSPP1 p.Pro1165Ser (c.3493C>T)** is classified **Benign/Likely benign** in CSPP1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.64%, mid); Associated with Joubert syndrome 21.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs200161440 · 9 submitters · 1 linked condition · low-frequency (popmax 1.64%, mid)

## For patients & families {#patients}

This is a change in the CSPP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, 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.Pro1165Ser |
| Coding change (HGVS c.) | c.3493C>T |
| MANE Select transcript | [NM_006421](https://www.ncbi.nlm.nih.gov/nuccore/NM_006421) (variant reported on NM_001382391) |
| dbSNP | [rs200161440](https://www.ncbi.nlm.nih.gov/snp/rs200161440/) |
| Variant type | single nucleotide variant |
| Location | chr8:67195405-67195405 (GRCh38) |
| ClinVar | [VCV383716](https://www.ncbi.nlm.nih.gov/clinvar/variation/383716/) |

**All HGVS expressions:** `NC_000008.10:g.68107640C>T`, `NC_000008.11:g.67195405C>T`, `NG_034100.1:g.136038C>T`, `NM_001291339.2:c.2443C>T`, `NM_001363131.2:c.3412C>T`, `NM_001363132.2:c.3298C>T`, `NM_001363133.2:c.3217C>T`, `NM_001364869.1:c.3559C>T`, `NM_001364870.1:c.3379C>T`, `NM_001382391.1:c.3493C>T`, `NM_001413186.1:c.5367+4991G>A`, `NM_001413187.1:c.5385+4991G>A`, `NM_001438330.1:c.3325C>T`, `NM_001438331.1:c.3339C>T`, `NM_001438332.1:c.2794C>T`, `NM_024790.7:c.3478C>T`

## 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 4.868, GERP 2.02, phastCons 0.877 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.11**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **1.64%** (mid) · FAF95 1.38% · FAF99 1.28% · 99/6,024 in the highest group · 1,458/1,613,936 alleles overall — low-frequency (popmax 1.64%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 1.64% | 61 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.44% | 69 |
| Admixed American | 0.282% | 355 |
| Remaining individuals (not grpmax-eligible) | 0.245% | 409 |
| African / African-American | 0.0653% | 1,531 |
| European (non-Finnish) | 0.0453% | 2,205 |
| South Asian | 0.0253% | 3,959 |
| East Asian | 0.00668% | 14,963 |

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (7 Likely benign, 2 Benign).

**Submission history:** 9 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-23 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-08-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Joubert syndrome 21, not provided, CSPP1-related disorder, not specified, none provided, CSPP1-related condition, AllHighlyPenetrant.

### 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 383716). 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.*