# NM_017950.4(CCDC40):c.1464del (p.Ser489fs)

https://sugi.bio/variant/ccdc40-p-ser489fs

## Summary

**CCDC40 p.Ser489fs (c.1464del)** is classified **Pathogenic** in CCDC40 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Very rare (popmax 0.000593%, nfe); Associated with primary ciliary dyskinesia.

**At a glance:** Pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the CCDC40 gene that is considered disease-causing, submitted by 2 submitters, and is linked to primary ciliary dyskinesia.

*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, X-linked recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-5 / 10 000 (Pakistan) |
| Clinical trials | 76 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CCDC40 is a diagnostic-grade gene on 6 Genomics England panels |

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

- Chronic otitis media — Frequent (79-30%)
- Recurrent otitis media — Frequent (79-30%)
- Nasal congestion — Frequent (79-30%)
- Chronic rhinitis — Frequent (79-30%)
- Neonatal respiratory distress — Frequent (79-30%)
- Male infertility — Frequent (79-30%)
- Recurrent sinopulmonary infections — Frequent (79-30%)
- Chronic sinusitis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004484/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CCDC40](https://sugi.bio/atlas/gene/CCDC40/) |
| Protein change (HGVS p.) | p.Ser489fs |
| Coding change (HGVS c.) | c.1464del |
| MANE Select transcript | [NM_017950](https://www.ncbi.nlm.nih.gov/nuccore/NM_017950) |
| Variant type | Deletion |
| Location | chr17:80065508-80065508 (GRCh38) |
| ClinVar | [VCV4074996](https://www.ncbi.nlm.nih.gov/clinvar/variation/4074996/) |

**All HGVS expressions:** `NC_000017.10:g.78039307del`, `NC_000017.11:g.80065508del`, `NG_029761.1:g.33877del`, `NM_001243342.2:c.1464del`, `NM_001330508.2:c.1464del`, `NM_017950.4:c.1464del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.587, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.962, pLI 2.6347e-28. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 20**, so the transcript is predicted to undergo NMD.
- 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,906 in the highest group · 7/1,460,934 alleles overall — very rare (popmax 0.000593%, nfe).

*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}

**CCDC40** population constraint: LOEUF 0.962, pLI 2.6347e-28, missense-Z 0.91122; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **primary ciliary dyskinesia 15** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.70, 24% of residues very-high.

**1 experimental structure(s)** (PDB): [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-03.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2019-12-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-03 |

## Associated conditions {#conditions}

[primary ciliary dyskinesia](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia/).

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia, Ciliary dyskinesia.

## Similar variants {#similar}

Related CCDC40 variant pages (same residue, condition, or type): [CCDC40 p.Ser489Arg](/variant/ccdc40-p-ser489arg), [CCDC40 p.Ser489Ile](/variant/ccdc40-p-ser489ile), [CCDC40 p.Ser489=](/variant/ccdc40-p-ser489), [CCDC40 p.Ala83fs](/variant/ccdc40-p-ala83fs), [CCDC40 p.Arg1053fs](/variant/ccdc40-p-arg1053fs), [CCDC40 p.Gln524fs](/variant/ccdc40-p-gln524fs), [CCDC40 p.Gly728fs](/variant/ccdc40-p-gly728fs), [CCDC40 p.Ile473fs](/variant/ccdc40-p-ile473fs).

### 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 4074996). 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.*