# NM_001378615.1(CC2D2A):c.2774G>C (p.Arg925Pro)

https://sugi.bio/variant/cc2d2a-p-arg925pro

## Summary

**CC2D2A p.Arg925Pro (c.2774G>C)** is classified **Conflicting classifications of pathogenicity** in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-07). AlphaMissense: likely pathogenic (0.8997); Very rare (popmax 0.00267%, afr); Associated with retinitis pigmentosa 93.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200707391 · 4 submitters · 6 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00267%, 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 retinitis pigmentosa 93.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | CC2D2A is a diagnostic-grade gene on 24 Genomics England panels |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025638/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.Arg925Pro |
| Coding change (HGVS c.) | c.2774G>C |
| MANE Select transcript | [NM_001378615](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378615) |
| dbSNP | [rs200707391](https://www.ncbi.nlm.nih.gov/snp/rs200707391/) |
| Variant type | single nucleotide variant |
| Location | chr4:15557452-15557452 (GRCh38) |
| ClinVar | [VCV937996](https://www.ncbi.nlm.nih.gov/clinvar/variation/937996/) |

**All HGVS expressions:** `LRG_697:g.92587G>C`, `LRG_697t1:c.2774G>C`, `NC_000004.11:g.15559075G>C`, `NC_000004.12:g.15557452G>C`, `NG_013035.1:g.92587G>C`, `NM_001080522.2:c.2774G>C`, `NM_001378615.1:c.2774G>C`, `NM_001378617.1:c.2627G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8997)
- REVEL 0.469 (indeterminate)
- SaProt LLR -8.042 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 9.872, GERP 2.01, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CC2D2A (of 9,494 modeled).
- CADD: **PHRED 27.8**. 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 0.96** across the covering region of the MANE Select transcript (15,475,933–15,580,102), spanning 104,169 bp. Chi-square p 0.09. 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,866 in the highest group · 2/1,612,496 alleles overall — very rare (popmax 0.00267%, afr).

*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}

Residue **925** lies in a UniProt-annotated variant site (in rp93).

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 2024-06-07.

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

**Submission history:** 4 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-04-19 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-24 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 93, Joubert syndrome, Meckel-Gruber syndrome, COACH syndrome 2, Joubert syndrome 9, Meckel syndrome, type 6, not provided, none provided, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis.

## Same-residue context {#hotspot}

Residue **925** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CC2D2A p.Arg925Ter](/variant/cc2d2a-p-arg925ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CC2D2A variant pages (same residue, condition, or type): [CC2D2A p.Arg925Ter](/variant/cc2d2a-p-arg925ter), [CC2D2A p.Arg925Gln](/variant/cc2d2a-p-arg925gln), [CC2D2A p.Arg925Leu](/variant/cc2d2a-p-arg925leu), [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).

### 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 937996). 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.*