# NM_021147.5(CCNO):c.203C>A (p.Ser68Ter)

https://sugi.bio/variant/ccno-p-ser68ter

## Summary

**CCNO p.Ser68Ter (c.203C>A)** is classified **Pathogenic** in CCNO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). No allele count reported in gnomAD v4.1 (AN 1,602,070); Associated with primary ciliary dyskinesia.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,602,070)

## For patients & families {#patients}

This is a change in the CCNO gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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 | CCNO is a diagnostic-grade gene on 4 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 | [CCNO](https://sugi.bio/atlas/gene/CCNO/) |
| Protein change (HGVS p.) | p.Ser68Ter |
| Coding change (HGVS c.) | c.203C>A |
| MANE Select transcript | [NM_021147](https://www.ncbi.nlm.nih.gov/nuccore/NM_021147) |
| Variant type | single nucleotide variant |
| Location | chr5:55233321-55233321 (GRCh38) |
| ClinVar | [VCV3727869](https://www.ncbi.nlm.nih.gov/clinvar/variation/3727869/) |

**All HGVS expressions:** `NC_000005.10:g.55233321G>T`, `NC_000005.9:g.54529149G>T`, `NG_034201.1:g.5397C>A`, `NG_173341.1:g.207G>T`, `NM_021147.5:c.203C>A`, `NR_125346.2:n.288C>A`, `NR_125347.2:n.288C>A`

## 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 9.78, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.698, pLI 3.3991e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 3**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 39.0**. 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** — 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: **no allele count reported in gnomAD v4.1 (AN 1,602,070)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CCNO** population constraint: LOEUF 1.698, pLI 3.3991e-10, missense-Z -1.8829. *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 29** — Definitive (AR)

## Protein context {#protein}

Residue **68** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 79.06, 59% of residues very-high.

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

*Describes the biological roles of CCNO (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional regulation of multiciliogenesis](https://reactome.org/content/detail/R-HSA-9945556) | curated |

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

**Biological process:** mitotic cell cycle, cilium assembly, multi-ciliated epithelial cell differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-31.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-31 |

## 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 CCNO variant pages (same residue, condition, or type): [CCNO p.Ser68=](/variant/ccno-p-ser68), [CCNO p.Gln103Ter](/variant/ccno-p-gln103ter), [CCNO p.Ala14Ser](/variant/ccno-p-ala14ser), [CCNO p.Ala202Val](/variant/ccno-p-ala202val), [CCNO p.Ala230Thr](/variant/ccno-p-ala230thr), [CCNO p.Ala258Gly](/variant/ccno-p-ala258gly), [CCNO p.Arg124Leu](/variant/ccno-p-arg124leu), [CCNO p.Arg124Trp](/variant/ccno-p-arg124trp).

### 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 3727869). 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.*