# NM_001378615.1(CC2D2A):c.4384T>C (p.Trp1462Arg)

https://sugi.bio/variant/cc2d2a-p-trp1462arg

## Summary

**CC2D2A p.Trp1462Arg (c.4384T>C)** is classified **Conflicting classifications of pathogenicity** in CC2D2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.9969); Very rare (popmax 0.00197%, amr); Associated with Meckel syndrome, type 6.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs368720062 · 3 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00197%, amr)

## 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 3 submitters, and is linked to Meckel syndrome, type 6.

*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/0015548/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.Trp1462Arg |
| Coding change (HGVS c.) | c.4384T>C |
| MANE Select transcript | [NM_001378615](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378615) |
| dbSNP | [rs368720062](https://www.ncbi.nlm.nih.gov/snp/rs368720062/) |
| Variant type | single nucleotide variant |
| Location | chr4:15596154-15596154 (GRCh38) |
| ClinVar | [VCV126244](https://www.ncbi.nlm.nih.gov/clinvar/variation/126244/) |

**All HGVS expressions:** `LRG_697:g.131289T>C`, `LRG_697t1:c.4384T>C`, `NC_000004.11:g.15597777T>C`, `NC_000004.12:g.15596154T>C`, `NG_013035.1:g.131289T>C`, `NM_001080522.2:c.4384T>C`, `NM_001378615.1:c.4384T>C`, `NM_001378617.1:c.4237T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9969)
- REVEL 0.838 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.618 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.895, GERP 2.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in CC2D2A (of 9,494 modeled).
- CADD: **PHRED 27.2**. 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 1.02** across the covering region of the MANE Select transcript (15,587,917–15,601,422), spanning 13,505 bp. Chi-square p 0.69. 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 **0.00197%** (amr) · FAF95 0.000633% · FAF99 0.000488% · 1/50,876 in the highest group · 15/1,550,016 alleles overall — very rare (popmax 0.00197%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00197% | 50,876 |
| South Asian | 0.00119% | 83,764 |
| European (non-Finnish) | 0.00113% | 88,170 |

*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 2025-06-06.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2013–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-18 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-06 |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2013-10-29 |

## Associated conditions {#conditions}

[Meckel syndrome, type 6](https://sugi.bio/atlas/disease/meckel-syndrome-type-6/), [Joubert syndrome 9](https://sugi.bio/atlas/disease/joubert-syndrome-9/), [Meckel syndrome](https://sugi.bio/atlas/disease/meckel-syndrome/), [retinitis pigmentosa 93](https://sugi.bio/atlas/disease/retinitis-pigmentosa-93/), [COACH syndrome 2](https://sugi.bio/atlas/disease/coach-syndrome-2/).

**Reported phenotype names (ClinVar):** Meckel syndrome, type 6, Meckel-Gruber syndrome, not provided, COACH syndrome 2, Joubert syndrome 9, Retinitis pigmentosa 93, none provided, Dysencephalia splachnocystica, DYSENCEPHALIA SPLANCHNOCYSTICA, GRUBER SYNDROME.

## Same-residue context {#hotspot}

Residue **1462** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CC2D2A p.Trp1462Ter](/variant/cc2d2a-p-trp1462ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CC2D2A variant pages (same residue, condition, or type): [CC2D2A p.Trp1462Ter](/variant/cc2d2a-p-trp1462ter), [CC2D2A c.1017+1G>A](/variant/cc2d2a-c-1017-plus-1g-a), [CC2D2A c.1149+1G>A](/variant/cc2d2a-c-1149-plus-1g-a), [CC2D2A c.123+2T>G](/variant/cc2d2a-c-123-plus-2t-g), [CC2D2A c.1359+1G>A](/variant/cc2d2a-c-1359-plus-1g-a), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 126244). 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.*