# NM_014008.5(CCDC22):c.615G>A (p.Ser205=)

https://sugi.bio/variant/ccdc22-p-ser205

## Summary

**CCDC22 p.Ser205= (c.615G>A)** is classified **Likely benign** in CCDC22 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). Rare (popmax 0.252%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs150796681 · 3 submitters · rare (popmax 0.252%, mid)

## For patients & families {#patients}

This is a change in the CCDC22 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CCDC22](https://sugi.bio/atlas/gene/CCDC22/) |
| Protein change (HGVS p.) | p.Ser205= |
| Coding change (HGVS c.) | c.615G>A |
| MANE Select transcript | [NM_014008](https://www.ncbi.nlm.nih.gov/nuccore/NM_014008) |
| dbSNP | [rs150796681](https://www.ncbi.nlm.nih.gov/snp/rs150796681/) |
| Variant type | single nucleotide variant |
| Location | chrX:49243363-49243363 (GRCh38) |
| ClinVar | [VCV547081](https://www.ncbi.nlm.nih.gov/clinvar/variation/547081/) |

**All HGVS expressions:** `NC_000023.10:g.49099829G>A`, `NC_000023.11:g.49243363G>A`, `NG_021311.2:g.12899G>A`, `NM_014008.5:c.615G>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 0.33) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -11.317, GERP -2.84 — fast-evolving / accelerated position
- CADD: **PHRED 0.455**. 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 **0.33**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**.
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.252%** (mid) · FAF95 0.142% · FAF99 0.109% · 11/4,357 in the highest group · 128/1,203,047 alleles overall — rare (popmax 0.252%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.252% | 396 |
| Remaining individuals (not grpmax-eligible) | 0.0296% | 3,379 |
| South Asian | 0.0162% | 6,175 |
| European (non-Finnish) | 0.00953% | 10,488 |
| African / African-American | 0.007% | 14,286 |
| Admixed American | 0.00665% | 15,044 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00458% | 21,846 |
| Finnish (not grpmax-eligible) | 0.00217% | 46,046 |

*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}


Curated gene–disease validity (ClinGen):

- **Ritscher-Schinzel syndrome 2** — Moderate (XL)

## Protein context {#protein}

Residue **205** lies in the 'sufficicient and required for interaction with ccdc93' region; an α-helix; the 'sufficient for interaction with commd1' region.

AlphaFold model confidence (whole protein): pLDDT 78.95, 36% of residues very-high.

**4 experimental structure(s)** (PDB): [8F2U](https://www.rcsb.org/structure/8F2U), [8P0V](https://www.rcsb.org/structure/8P0V), [8P0W](https://www.rcsb.org/structure/8P0W), [8P0X](https://www.rcsb.org/structure/8P0X).

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

*Describes the biological roles of CCDC22 (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.*

**How this variant is thought to act:** CCDC22's established molecular role includes cullin family protein binding. p.Ser205= falls in the sufficicient and required for interaction with ccdc93 region.


### Pathways affected {#pathways}

CCDC22 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cullin family protein binding.

**Biological process:** intracellular copper ion homeostasis, Golgi to plasma membrane transport, endocytic recycling, positive regulation of canonical NF-kappaB signal transduction, negative regulation of canonical NF-kappaB signal transduction, positive regulation of ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CCDC22 variant pages (same residue, condition, or type): [CCDC22 p.Ser205Leu](/variant/ccdc22-p-ser205leu), [CCDC22 p.Ala463Gly](/variant/ccdc22-p-ala463gly), [CCDC22 p.Arg107Cys](/variant/ccdc22-p-arg107cys), [CCDC22 p.Arg128Gln](/variant/ccdc22-p-arg128gln), [CCDC22 p.Arg135Gln](/variant/ccdc22-p-arg135gln), [CCDC22 p.Arg148Cys](/variant/ccdc22-p-arg148cys), [CCDC22 p.Arg245Gln](/variant/ccdc22-p-arg245gln), [CCDC22 p.Arg257His](/variant/ccdc22-p-arg257his).

### 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 547081). 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.*