# NM_001378615.1(CC2D2A):c.2007G>A (p.Ala669=)

https://sugi.bio/variant/cc2d2a-p-ala669

## Summary

**CC2D2A p.Ala669= (c.2007G>A)** is classified **Conflicting classifications of pathogenicity** in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-02). Ultra-rare (popmax 0.0549%, afr); Associated with Meckel syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs376644970 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0549%, afr)

## For patients & families {#patients}

This is a change in the CC2D2A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Meckel 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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003436/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.Ala669= |
| Coding change (HGVS c.) | c.2007G>A |
| MANE Select transcript | [NM_001378615](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378615) |
| dbSNP | [rs376644970](https://www.ncbi.nlm.nih.gov/snp/rs376644970/) |
| Variant type | single nucleotide variant |
| Location | chr4:15540840-15540840 (GRCh38) |
| ClinVar | [VCV287925](https://www.ncbi.nlm.nih.gov/clinvar/variation/287925/) |

**All HGVS expressions:** `LRG_697:g.75975G>A`, `LRG_697t1:c.2007G>A`, `NC_000004.11:g.15542463G>A`, `NC_000004.12:g.15540840G>A`, `NG_013035.1:g.75975G>A`, `NM_001080522.2:c.2007G>A`, `NM_001378615.1:c.2007G>A`, `NM_001378617.1:c.1860G>A`

## 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 0.36) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.711, GERP -4.41 — fast-evolving / accelerated position
- CADD: **PHRED 12.3**. 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 **0.03**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0549%** (afr) · FAF95 0.0415% · FAF99 0.0369% · 41/74,714 in the highest group · 75/1,596,884 alleles overall — ultra-rare (popmax 0.0549%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0549% | 1,822 |
| Admixed American | 0.0294% | 3,398 |
| South Asian | 0.00685% | 14,592 |
| East Asian | 0.00226% | 44,266 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 61,944 |
| European (non-Finnish) | 0.000768% | 130,158 |

*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 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):

- **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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-02.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-02 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-02-07 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Meckel-Gruber syndrome, not provided, Joubert syndrome, not specified, DYSENCEPHALIA SPLANCHNOCYSTICA, GRUBER SYNDROME, Dysencephalia splachnocystica, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis, none provided.

## Similar variants {#similar}

Related CC2D2A variant pages (same residue, condition, or type): [CC2D2A p.Ala669Glu](/variant/cc2d2a-p-ala669glu), [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).

### 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 287925). 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.*