# NM_032040.5(CCDC8):c.1555del (p.Arg519fs)

https://sugi.bio/variant/ccdc8-p-arg519fs

## Summary

**CCDC8 p.Arg519fs (c.1555del)** is classified **Uncertain significance** in CCDC8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-29). Ultra-rare (popmax 0.0336%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs745914961 · 4 submitters · ultra-rare (popmax 0.0336%, nfe)

## For patients & families {#patients}

This is a change in the CCDC8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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 | [CCDC8](https://sugi.bio/atlas/gene/CCDC8/) |
| Protein change (HGVS p.) | p.Arg519fs |
| Coding change (HGVS c.) | c.1555del |
| MANE Select transcript | [NM_032040](https://www.ncbi.nlm.nih.gov/nuccore/NM_032040) |
| dbSNP | [rs745914961](https://www.ncbi.nlm.nih.gov/snp/rs745914961/) |
| Variant type | Deletion |
| Location | chr19:46411256-46411256 (GRCh38) |
| ClinVar | [VCV452737](https://www.ncbi.nlm.nih.gov/clinvar/variation/452737/) |

**All HGVS expressions:** `LRG_1258:g.7407del`, `LRG_1258t1:c.1555del`, `NC_000019.10:g.46411256del`, `NC_000019.9:g.46914513del`, `NG_031956.1:g.7407del`, `NM_032040.5:c.1555del`, `NM_032040.5:c.1555delA`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 1.651, GERP 0.652, phastCons 0.02 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.796, pLI 0.0017454. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 22.6**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0336%** (nfe) · FAF95 0.0309% · FAF99 0.0298% · 397/1,180,026 in the highest group · 435/1,614,078 alleles overall — ultra-rare (popmax 0.0336%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0642% | 1,558 |
| European (non-Finnish) (grpmax) | 0.0336% | 2,972 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,905 |
| African / African-American | 0.00267% | 37,470 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,046 |

Ashkenazi Jewish 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}

**CCDC8** population constraint: LOEUF 1.796, pLI 0.0017454, missense-Z -0.12651; 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 46.83, 0% of residues very-high.

**1 experimental structure(s)** (PDB): [4LG6](https://www.rcsb.org/structure/4LG6).

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

*Describes the biological roles of CCDC8 (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}

CCDC8 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Biological process:** microtubule cytoskeleton organization, regulation of mitotic nuclear division.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-29.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-29 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-10 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-10-10 |

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

## Similar variants {#similar}

Related CCDC8 variant pages (same residue, condition, or type): [CCDC8 p.Gln327fs](/variant/ccdc8-p-gln327fs), [CCDC8 p.Glu337_Arg344del](/variant/ccdc8-p-glu337-arg344del), [CCDC8 p.Glu350_Ala373del](/variant/ccdc8-p-glu350-ala373del), [CCDC8 p.Ala323fs](/variant/ccdc8-p-ala323fs), [CCDC8 p.Ala353fs](/variant/ccdc8-p-ala353fs), [CCDC8 p.Asp247fs](/variant/ccdc8-p-asp247fs), [CCDC8 p.Gln68fs](/variant/ccdc8-p-gln68fs), [CCDC8 p.Gly95fs](/variant/ccdc8-p-gly95fs).

### 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 452737). 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.*