# NM_001384732.1(CPLANE1):c.3709T>C (p.Phe1237Leu)

https://sugi.bio/variant/cplane1-p-phe1237leu

## Summary

**CPLANE1 p.Phe1237Leu (c.3709T>C)** is classified **Uncertain significance** in CPLANE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely pathogenic (0.824); Ultra-rare (popmax 0.0174%, afr); Associated with Joubert syndrome 17.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0174%, afr)

## 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 1 submitter, 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.Phe1237Leu |
| Coding change (HGVS c.) | c.3709T>C |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| Variant type | single nucleotide variant |
| Location | chr5:37195960-37195960 (GRCh38) |
| ClinVar | [VCV3592494](https://www.ncbi.nlm.nih.gov/clinvar/variation/3592494/) |

**All HGVS expressions:** `NC_000005.10:g.37195960A>G`, `NC_000005.9:g.37196062A>G`, `NG_032772.2:g.58469T>C`, `NG_032772.3:g.58416T>C`, `NM_001384732.1:c.3709T>C`, `NM_023073.3:c.3709T>C`, `NM_023073.4:c.3709T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.824)
- REVEL 0.042 (moderately benign-leaning) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL does not; SaProt makes no call
- Conservation: phyloP 9.209, GERP 1.69, phastCons 1 — highly conserved (agrees)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CPLANE1 (of 18,722 modeled).
- CADD: **PHRED 21.4**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (afr) · FAF95 0.0103% · FAF99 0.00814% · 13/74,810 in the highest group · 14/1,610,582 alleles overall — ultra-rare (popmax 0.0174%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0174% | 5,755 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,300 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-28 |

## Associated conditions {#conditions}

[Joubert syndrome 17](https://sugi.bio/atlas/disease/joubert-syndrome-17/), [orofaciodigital syndrome type 6](https://sugi.bio/atlas/disease/orofaciodigital-syndrome-type-6/).

**Reported phenotype names (ClinVar):** Joubert syndrome 17, Orofaciodigital syndrome type 6, OROFACIODIGITAL SYNDROME VI, OFDS VI, POLYDACTYLY, CLEFT LIP/PALATE OR LINGUAL LUMP, AND PSYCHOMOTOR RETARDATION, VARADI SYNDROME, VARADI-PAPP SYNDROME, Oral-facial-digital syndrome type 6, Central polydactyly cleft lip/palate or lingual lump and psychomotor retardation, Y-shaped central metacarpal and cerebellar defect.

## 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.3290-2A>G](/variant/cplane1-c-3290-minus-2a-g), [CPLANE1 c.3673-1G>C](/variant/cplane1-c-3673-minus-1g-c), [CPLANE1 c.677+1G>C](/variant/cplane1-c-677-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3592494). 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.*