# NM_001384732.1(CPLANE1):c.6006A>G (p.Lys2002=)

https://sugi.bio/variant/cplane1-p-lys2002

## Summary

**CPLANE1 p.Lys2002= (c.6006A>G)** is classified **Likely benign** in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0187%, afr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs777584963 · 2 submitters · ultra-rare (popmax 0.0187%, afr)

## For patients & families {#patients}

This is a change in the CPLANE1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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:** [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.Lys2002= |
| Coding change (HGVS c.) | c.6006A>G |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| dbSNP | [rs777584963](https://www.ncbi.nlm.nih.gov/snp/rs777584963/) |
| Variant type | single nucleotide variant |
| Location | chr5:37173920-37173920 (GRCh38) |
| ClinVar | [VCV2063534](https://www.ncbi.nlm.nih.gov/clinvar/variation/2063534/) |

**All HGVS expressions:** `NC_000005.10:g.37173920T>C`, `NC_000005.9:g.37174022T>C`, `NG_032772.3:g.80456A>G`, `NM_001384732.1:c.6006A>G`, `NM_023073.4:c.6006A>G`

## 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 -5.434, GERP -2.71 — fast-evolving / accelerated position
- CADD: **PHRED 0.557**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.24 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0187%** (afr) · FAF95 0.0112% · FAF99 0.00905% · 14/74,922 in the highest group · 15/1,614,000 alleles overall — ultra-rare (popmax 0.0187%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0187% | 5,352 |
| European (non-Finnish) | 8.47e-05% | 1,180,013 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-18 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |

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

## Similar variants {#similar}

Related CPLANE1 variant pages (same residue, condition, or type): [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.2920+1G>A](/variant/cplane1-c-2920-plus-1g-a), [CPLANE1 c.3290-2A>G](/variant/cplane1-c-3290-minus-2a-g), [CPLANE1 c.3673-1G>C](/variant/cplane1-c-3673-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2063534). 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.*