# NM_001378030.1(CCDC78):c.862C>A (p.Arg288Ser)

https://sugi.bio/variant/ccdc78-p-arg288ser

## Summary

**CCDC78 p.Arg288Ser (c.862C>A)** is classified **Uncertain significance** in CCDC78 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8818); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs764179609 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CCDC78 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [CCDC78](https://sugi.bio/atlas/gene/CCDC78/) |
| Protein change (HGVS p.) | p.Arg288Ser |
| Coding change (HGVS c.) | c.862C>A |
| MANE Select transcript | [NM_001378030](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378030) |
| dbSNP | [rs764179609](https://www.ncbi.nlm.nih.gov/snp/rs764179609/) |
| Variant type | single nucleotide variant |
| Location | chr16:724413-724413 (GRCh38) |
| ClinVar | [VCV2720308](https://www.ncbi.nlm.nih.gov/clinvar/variation/2720308/) |

**All HGVS expressions:** `LRG_705:g.7061C>A`, `LRG_705t1:c.862C>A`, `LRG_705t2:c.862C>A`, `NC_000016.10:g.724413G>T`, `NC_000016.9:g.774413G>T`, `NG_032932.1:g.7061C>A`, `NM_001031737.2:c.862C>A`, `NM_001031737.3:c.862C>A`, `NM_001378030.1:c.862C>A`, `NM_001378031.1:c.862C>A`, `NM_001378033.1:c.295C>A`, `NR_165382.1:n.1419C>A`, `NR_165383.1:n.1065C>A`, `NR_165384.1:n.1030C>A`, `NR_165385.1:n.1130C>A`, `NR_165386.1:n.1197C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8818)
- REVEL 0.352 (indeterminate)
- SaProt LLR -7.483 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 5.789, GERP -0.467, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in CCDC78 (of 2,542 modeled).
- CADD: **PHRED 24.9**. 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.*
- Regional missense constraint: **o/e 1.20** across the covering region of the MANE Select transcript (722,681–726,367), spanning 3,686 bp. Chi-square p 9.6e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.28 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,950 in the highest group · 1/1,457,696 alleles overall — very rare (popmax 8.47e-05%, 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}

**CCDC78** population constraint: LOEUF 1.615, pLI 1.0158e-33, missense-Z -2.0179. *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):

- **centronuclear myopathy** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 66.65, 29% of residues very-high.

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

*Describes the biological roles of CCDC78 (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}

CCDC78 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:** skeletal muscle contraction, de novo centriole assembly involved in multi-ciliated epithelial cell differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [congenital myopathy with internal nuclei and atypical cores](https://sugi.bio/atlas/disease/congenital-myopathy-with-internal-nuclei-and-atypical-cores/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Congenital myopathy with internal nuclei and atypical cores, Myopathy, centronuclear, 4.

## Similar variants {#similar}

Related CCDC78 variant pages (same residue, condition, or type): [CCDC78 p.Arg288Cys](/variant/ccdc78-p-arg288cys), [CCDC78 p.Arg288His](/variant/ccdc78-p-arg288his), [CCDC78 c.1053+1G>A](/variant/ccdc78-c-1053-plus-1g-a), [CCDC78 c.268-3C>T](/variant/ccdc78-c-268-minus-3c-t), [CCDC78 c.61-1G>A](/variant/ccdc78-c-61-minus-1g-a), [CCDC78 c.61-6C>A](/variant/ccdc78-c-61-minus-6c-a), [CCDC78 c.953+1G>A](/variant/ccdc78-c-953-plus-1g-a), [CCDC78 p.Ala126Val](/variant/ccdc78-p-ala126val).

### 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 2720308). 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.*