# NM_001378615.1(CC2D2A):c.590T>C (p.Phe197Ser)

https://sugi.bio/variant/cc2d2a-p-phe197ser

## Summary

**CC2D2A p.Phe197Ser (c.590T>C)** is classified **Uncertain significance** in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-13). AlphaMissense: likely benign (0.2362); Very rare (popmax 0.00349%, nfe); Associated with Meckel syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs200761243 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00349%, nfe)

## 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 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.Phe197Ser |
| Coding change (HGVS c.) | c.590T>C |
| MANE Select transcript | [NM_001378615](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378615) |
| dbSNP | [rs200761243](https://www.ncbi.nlm.nih.gov/snp/rs200761243/) |
| Variant type | single nucleotide variant |
| Location | chr4:15511296-15511296 (GRCh38) |
| ClinVar | [VCV1500240](https://www.ncbi.nlm.nih.gov/clinvar/variation/1500240/) |

**All HGVS expressions:** `LRG_697:g.46431T>C`, `LRG_697t1:c.590T>C`, `NC_000004.11:g.15512919T>C`, `NC_000004.12:g.15511296T>C`, `NG_013035.1:g.46431T>C`, `NM_001080522.2:c.590T>C`, `NM_001378615.1:c.590T>C`, `NM_001378617.1:c.443T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2362)
- REVEL 0.104 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.824 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.938, GERP 2.6, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.28 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00349%** (nfe) · FAF95 0.0026% · FAF99 0.00234% · 41/1,174,882 in the highest group · 46/1,600,864 alleles overall — very rare (popmax 0.00349%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00627% | 15,949 |
| European (non-Finnish) (grpmax) | 0.00349% | 28,656 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,910 |

Finnish 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}

**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}

Residue **197** lies in the 'disordered' region.

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 2022-01-13.

**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 | 2022-01-13 |

## 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, Joubert syndrome, DYSENCEPHALIA SPLANCHNOCYSTICA, GRUBER SYNDROME, Dysencephalia splachnocystica, CEREBELLOPARENCHYMAL DISORDER IV, JOUBERT-BOLTSHAUSER SYNDROME, Familial aplasia of the vermis.

## 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 2026-10-14); 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 2026-07-14); 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 1500240). 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.*