# NM_001384732.1(CPLANE1):c.221C>T (p.Ala74Val)

https://sugi.bio/variant/cplane1-p-ala74val

## Summary

**CPLANE1 p.Ala74Val (c.221C>T)** is classified **Conflicting classifications of pathogenicity** in CPLANE1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0986); Ultra-rare (popmax 0.0218%, nfe); Associated with Joubert syndrome 17.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139496915 · 8 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0218%, nfe)

## For patients & families {#patients}

This is a change in the CPLANE1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 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.Ala74Val |
| Coding change (HGVS c.) | c.221C>T |
| MANE Select transcript | [NM_001384732](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384732) |
| dbSNP | [rs139496915](https://www.ncbi.nlm.nih.gov/snp/rs139496915/) |
| Variant type | single nucleotide variant |
| Location | chr5:37245595-37245595 (GRCh38) |
| ClinVar | [VCV197337](https://www.ncbi.nlm.nih.gov/clinvar/variation/197337/) |

**All HGVS expressions:** `NC_000005.10:g.37245595G>A`, `NC_000005.9:g.37245697G>A`, `NG_032772.2:g.8834C>T`, `NM_001384732.1:c.221C>T`, `NM_023073.4:c.221C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0986)
- REVEL 0.057 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.724, GERP 1.73, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.98**. 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 **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0218%** (nfe) · FAF95 0.0195% · FAF99 0.0187% · 246/1,128,236 in the highest group · 300/1,506,938 alleles overall — ultra-rare (popmax 0.0218%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.115% | 873 |
| European (non-Finnish) (grpmax) | 0.0218% | 4,586 |
| Remaining individuals (not grpmax-eligible) | 0.019% | 5,276 |
| Middle Eastern | 0.0172% | 5,802 |
| Admixed American | 0.0142% | 7,021 |
| African / African-American | 0.00423% | 23,656 |
| Finnish (not grpmax-eligible) | 0.0034% | 29,415 |

Ashkenazi Jewish 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.*

## 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (5 Uncertain significance, 3 Likely benign).

**Submission history:** 8 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-07 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-15 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-01 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-05-10 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-11-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-18 |

## 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, not provided, Inborn genetic diseases, Orofaciodigital syndrome type 6, CPLANE1-related disorder, not specified, CPLANE1-related condition, OROFACIODIGITAL SYNDROME VI, OFDS VI, POLYDACTYLY, CLEFT LIP/PALATE OR LINGUAL LUMP, AND PSYCHOMOTOR RETARDATION.

## Similar variants {#similar}

Related CPLANE1 variant pages (same residue, condition, or type): [CPLANE1 p.Ala74=](/variant/cplane1-p-ala74), [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).

### 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 197337). 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.*