# NM_001384732.1(CPLANE1):c.2932C>T (p.Arg978Ter)

https://sugi.bio/variant/cplane1-p-arg978ter

## Summary

**CPLANE1 p.Arg978Ter (c.2932C>T)** is classified **Pathogenic** in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-06). Very rare (popmax 0.00244%, eas); Associated with Joubert syndrome 17.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1359437084 · 2 submitters · 1 linked condition · very rare (popmax 0.00244%, eas)

## For patients & families {#patients}

This is a change in the CPLANE1 gene that is considered disease-causing, submitted by 2 submitters, and is linked to Joubert syndrome 17.

*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/0015824/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.Arg978Ter |
| Coding change (HGVS c.) | c.2932C>T |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| dbSNP | [rs1359437084](https://www.ncbi.nlm.nih.gov/snp/rs1359437084/) |
| Variant type | single nucleotide variant |
| Location | chr5:37206414-37206414 (GRCh38) |
| ClinVar | [VCV846826](https://www.ncbi.nlm.nih.gov/clinvar/variation/846826/) |

**All HGVS expressions:** `NC_000005.10:g.37206414G>A`, `NC_000005.9:g.37206516G>A`, `NG_032772.2:g.48015C>T`, `NM_001384732.1:c.2932C>T`, `NM_023073.4:c.2932C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.30) — consistent with the pathogenic call
- Conservation: phyloP 4.393, GERP 0.17, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 17 of 53**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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 deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**.
- Pangolin: Δ**0.40** (loss), gain 0.11 / loss 0.40. 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 **0.00244%** (eas) · FAF95 2.9e-05% · FAF99 1.1e-05% · 1/40,914 in the highest group · 4/1,397,156 alleles overall — very rare (popmax 0.00244%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00244% | 40,914 |
| South Asian | 0.00119% | 84,004 |
| European (non-Finnish) | 0.000175% | 572,466 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-05-06.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2020–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-08-07 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-06 |

## Associated conditions {#conditions}

[Joubert syndrome 17](https://sugi.bio/atlas/disease/joubert-syndrome-17/).

**Reported phenotype names (ClinVar):** Joubert syndrome 17, not provided, none provided.

## Similar variants {#similar}

Related CPLANE1 variant pages (same residue, condition, or type): [CPLANE1 p.Arg978Gln](/variant/cplane1-p-arg978gln), [CPLANE1 p.Arg978=](/variant/cplane1-p-arg978), [CPLANE1 c.1372-2A>G](/variant/cplane1-c-1372-minus-2a-g), [CPLANE1 c.2291+1G>A](/variant/cplane1-c-2291-plus-1g-a), [CPLANE1 c.2291+2T>C](/variant/cplane1-c-2291-plus-2t-c), [CPLANE1 c.2292-1G>A](/variant/cplane1-c-2292-minus-1g-a), [CPLANE1 c.2500+1G>A](/variant/cplane1-c-2500-plus-1g-a), [CPLANE1 c.3290-2A>G](/variant/cplane1-c-3290-minus-2a-g).

### 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 846826). 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.*