# NM_001330691.3(CEP78):c.211del (p.Val71fs)

https://sugi.bio/variant/cep78-p-val71fs

## Summary

**CEP78 p.Val71fs (c.211del)** is classified **Likely pathogenic** in CEP78 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). Very rare (popmax 8.58e-05%, nfe); Associated with CEP78-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1363491382 · 1 submitter · 1 linked condition · very rare (popmax 8.58e-05%, nfe)

## For patients & families {#patients}

This is a change in the CEP78 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to CEP78-related disorder.

*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 | [CEP78](https://sugi.bio/atlas/gene/CEP78/) |
| Protein change (HGVS p.) | p.Val71fs |
| Coding change (HGVS c.) | c.211del |
| MANE Select transcript | [NM_001330691](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330691) |
| dbSNP | [rs1363491382](https://www.ncbi.nlm.nih.gov/snp/rs1363491382/) |
| Variant type | Deletion |
| Location | chr9:78236560-78236560 (GRCh38) |
| ClinVar | [VCV867155](https://www.ncbi.nlm.nih.gov/clinvar/variation/867155/) |

**All HGVS expressions:** `NC_000009.11:g.80851477del`, `NC_000009.12:g.78236561del`, `NG_053171.1:g.5500del`, `NM_001098802.3:c.211del`, `NM_001330691.3:c.211del`, `NM_001330693.3:c.211del`, `NM_001330694.2:c.211del`, `NM_001349838.2:c.211del`, `NM_001349839.2:c.211del`, `NM_001349840.2:c.211del`, `NM_032171.3:c.211del`

## 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 2.132, GERP -2.69, phastCons 0.044 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.531, pLI 7.6315e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 17**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 23.6**. 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 **8.58e-05%** (nfe) · 1/1,165,528 in the highest group · 2/1,585,176 alleles overall — very rare (popmax 8.58e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 60,952 |
| European (non-Finnish) (grpmax) | 8.58e-05% | 1,165,528 |

Remaining individuals 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}

**CEP78** population constraint: LOEUF 1.531, pLI 7.6315e-18, missense-Z -1.0296; 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):

- **cone-rod dystrophy and hearing loss** — Strong (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.28, 30% of residues very-high.

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

*Describes the biological roles of CEP78 (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}

CEP78 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | other |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | other |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | other |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | other |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | other |

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

**Biological process:** flagellated sperm motility, negative regulation of protein ubiquitination, cilium organization, protein localization to centrosome.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-20.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-06-20 |

## Associated conditions {#conditions}

[CEP78-related disorder](https://sugi.bio/atlas/disease/cep78-related-disorder/).

**Reported phenotype names (ClinVar):** CEP78-related disorder, CEP78-related condition.

## Similar variants {#similar}

Related CEP78 variant pages (same residue, condition, or type): [CEP78 p.Glu472fs](/variant/cep78-p-glu472fs), [CEP78 p.Lys179fs](/variant/cep78-p-lys179fs), [CEP78 p.Ser485fs](/variant/cep78-p-ser485fs), [CEP78 p.Trp212fs](/variant/cep78-p-trp212fs), [CEP78 p.Asp67fs](/variant/cep78-p-asp67fs), [CEP78 p.Gly241fs](/variant/cep78-p-gly241fs), [CEP78 p.Gly420fs](/variant/cep78-p-gly420fs), [CEP78 p.Phe15fs](/variant/cep78-p-phe15fs).

### 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 867155). 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.*