# NM_001384732.1(CPLANE1):c.2182C>G (p.Pro728Ala)

https://sugi.bio/variant/cplane1-p-pro728ala

## Summary

**CPLANE1 p.Pro728Ala (c.2182C>G)** is classified **Uncertain significance** in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-12). AlphaMissense: likely benign (0.2529); Very rare (popmax 0.00148%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1467926733 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.00148%, nfe)

## For patients & families {#patients}

This is a change in the CPLANE1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro728Ala |
| Coding change (HGVS c.) | c.2182C>G |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| dbSNP | [rs1467926733](https://www.ncbi.nlm.nih.gov/snp/rs1467926733/) |
| Variant type | single nucleotide variant |
| Location | chr5:37226413-37226413 (GRCh38) |
| ClinVar | [VCV434553](https://www.ncbi.nlm.nih.gov/clinvar/variation/434553/) |

**All HGVS expressions:** `NC_000005.10:g.37226413G>C`, `NC_000005.9:g.37226515G>C`, `NG_032772.2:g.28016C>G`, `NM_001384732.1:c.2182C>G`, `NM_023073.4:c.2182C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2529)
- REVEL 0.299 (indeterminate)
- SpliceAI predicts **acceptor loss** (Δ 0.60) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.566, GERP 0.54, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.9**. 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 0.92** across the covering region of the MANE Select transcript (37,108,429–37,247,698), spanning 139,269 bp. Chi-square p 2.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.60**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 12 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00148%** (nfe) · FAF95 0.000903% · FAF99 0.000738% · 17/1,146,578 in the highest group · 17/1,550,168 alleles overall — very rare (popmax 0.00148%, nfe).

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-07-12.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2016–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-08-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-12 |

**Reported phenotype names (ClinVar):** not specified, not provided, AllHighlyPenetrant, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CPLANE1 variant pages (same residue, condition, or type): [CPLANE1 p.Pro728Leu](/variant/cplane1-p-pro728leu), [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).

### 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 434553). 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.*