# NM_001378615.1(CC2D2A):c.918C>T (p.Pro306=)

https://sugi.bio/variant/cc2d2a-p-pro306

## Summary

**CC2D2A p.Pro306= (c.918C>T)** is classified **Uncertain significance** in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-02). Absent from gnomAD v4.1; Associated with Joubert syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1716840860 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CC2D2A 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.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006802/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CC2D2A](https://sugi.bio/atlas/gene/CC2D2A/) |
| Protein change (HGVS p.) | p.Pro306= |
| Coding change (HGVS c.) | c.918C>T |
| MANE Select transcript | [NM_001378615](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378615) |
| dbSNP | [rs1716840860](https://www.ncbi.nlm.nih.gov/snp/rs1716840860/) |
| Variant type | single nucleotide variant |
| Location | chr4:15515905-15515905 (GRCh38) |
| ClinVar | [VCV2021003](https://www.ncbi.nlm.nih.gov/clinvar/variation/2021003/) |

**All HGVS expressions:** `LRG_697:g.51040C>T`, `LRG_697t1:c.918C>T`, `NC_000004.11:g.15517528C>T`, `NC_000004.12:g.15515905C>T`, `NG_013035.1:g.51040C>T`, `NM_001080522.2:c.918C>T`, `NM_001378615.1:c.918C>T`, `NM_001378617.1:c.771C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.049, GERP -5.53, phastCons 0.511 — weakly conserved position
- CADD: **PHRED 11.88**. 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 **0.16**, donor loss **0.02**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CC2D2A** population constraint: LOEUF 0.854, pLI 6.8922e-26, missense-Z 0.46757; 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):

- **ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.46, 13% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CC2D2A (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CC2D2A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Joubert syndrome, Meckel-Gruber syndrome, CEREBELLOPARENCHYMAL DISORDER IV, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis, DYSENCEPHALIA SPLANCHNOCYSTICA, GRUBER SYNDROME, Dysencephalia splachnocystica.

## Similar variants {#similar}

Related CC2D2A variant pages (same residue, condition, or type): [CC2D2A c.1017+1G>A](/variant/cc2d2a-c-1017-plus-1g-a), [CC2D2A c.123+2T>G](/variant/cc2d2a-c-123-plus-2t-g), [CC2D2A c.1359+1G>C](/variant/cc2d2a-c-1359-plus-1g-c), [CC2D2A c.1466+1G>A](/variant/cc2d2a-c-1466-plus-1g-a), [CC2D2A c.1466+2T>C](/variant/cc2d2a-c-1466-plus-2t-c), [CC2D2A c.1608-2A>G](/variant/cc2d2a-c-1608-minus-2a-g), [CC2D2A c.2004-17A>G](/variant/cc2d2a-c-2004-minus-17a-g), [CC2D2A c.2486+1G>A](/variant/cc2d2a-c-2486-plus-1g-a).

### 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 2021003). 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.*