# NM_001382391.1(CSPP1):c.2980C>T (p.Arg994Ter)

https://sugi.bio/variant/cspp1-p-arg994ter

## Summary

**CSPP1 p.Arg994Ter (c.2980C>T)** is classified **Pathogenic** in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). Very rare (popmax 0.00134%, afr); Associated with Joubert syndrome 21.

**At a glance:** Pathogenic · review: Single submitter · rsID rs760275528 · 1 submitter · 1 linked condition · very rare (popmax 0.00134%, afr)

## 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.Arg994Ter |
| Coding change (HGVS c.) | c.2980C>T |
| MANE Select transcript | [NM_006421](https://www.ncbi.nlm.nih.gov/nuccore/NM_006421) (variant reported on NM_001382391) |
| dbSNP | [rs760275528](https://www.ncbi.nlm.nih.gov/snp/rs760275528/) |
| Variant type | single nucleotide variant |
| Location | chr8:67175307-67175307 (GRCh38) |
| ClinVar | [VCV1069030](https://www.ncbi.nlm.nih.gov/clinvar/variation/1069030/) |

**All HGVS expressions:** `NC_000008.10:g.68087542C>T`, `NC_000008.11:g.67175307C>T`, `NG_034100.1:g.115940C>T`, `NM_001291339.2:c.1930C>T`, `NM_001363131.2:c.2899C>T`, `NM_001363132.2:c.2785C>T`, `NM_001363133.2:c.2704C>T`, `NM_001364869.1:c.3046C>T`, `NM_001364870.1:c.2866C>T`, `NM_001382391.1:c.2980C>T`, `NM_001413186.1:c.*248G>A`, `NM_001413187.1:c.*248G>A`, `NM_001438330.1:c.2812C>T`, `NM_001438331.1:c.2965C>T`, `NM_001438332.1:c.2281C>T`, `NM_024790.7:c.2965C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.263, GERP 1.4, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 38.0**. 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.*
- 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 **0.00134%** (afr) · FAF95 0.000124% · FAF99 9e-05% · 1/74,728 in the highest group · 8/1,456,880 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,280 |
| African / African-American (grpmax) | 0.00134% | 74,728 |
| South Asian | 0.0011% | 90,500 |
| European (non-Finnish) | 0.000425% | 235,460 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-07 |

## Associated conditions {#conditions}

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

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

### 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 1069030). 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.*