# NM_024899.4(CEP76):c.307C>T (p.Pro103Ser)

https://sugi.bio/variant/cep76-p-pro103ser

## Summary

**CEP76 p.Pro103Ser (c.307C>T)** is classified **Pathogenic** in CEP76 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-29). AlphaMissense: likely benign (0.3212); Absent from gnomAD v4.1; Associated with Joubert syndrome 1.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CEP76 gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 1 submitter, and is linked to Joubert syndrome 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024643/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CEP76](https://sugi.bio/atlas/gene/CEP76/) |
| Protein change (HGVS p.) | p.Pro103Ser |
| Coding change (HGVS c.) | c.307C>T |
| MANE Select transcript | [NM_024899](https://www.ncbi.nlm.nih.gov/nuccore/NM_024899) |
| Variant type | single nucleotide variant |
| Location | chr18:12699192-12699192 (GRCh38) |
| ClinVar | [VCV4075828](https://www.ncbi.nlm.nih.gov/clinvar/variation/4075828/) |

**All HGVS expressions:** `NC_000018.10:g.12699192G>A`, `NC_000018.9:g.12699191G>A`, `NM_001271989.2:c.295+638C>T`, `NM_024899.4:c.307C>T`, `NM_147163.2:c.-36-7358G>A`, `NR_073537.1:n.531C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.3212) — ⚠ discordant with the pathogenic call
- REVEL 0.42 (indeterminate)
- SaProt LLR -7.385 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.752, GERP 1.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.8**. 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 0.87** across the covering region of the MANE Select transcript (12,673,368–12,702,548), spanning 29,180 bp. Chi-square p 0.00019. 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, Δ0.22 acceptor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CEP76** population constraint: LOEUF 0.716, pLI 0.00038446, missense-Z 1.6558. *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 87.18, 69% of residues very-high.

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

*Describes the biological roles of CEP76 (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}

CEP76 participates in **7 Reactome pathways** (⚕ = disease pathway):

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

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

**Biological process:** regulation of centriole replication.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago | Pathogenic | criteria provided, single submitter | research | 2024-07-29 |

## Associated conditions {#conditions}

[Joubert syndrome 1](https://sugi.bio/atlas/disease/joubert-syndrome-1/).

**Reported phenotype names (ClinVar):** Joubert syndrome 1, Cerebellooculorenal syndrome 1, CEREBELLOPARENCHYMAL DISORDER IV.

## Similar variants {#similar}

Related CEP76 variant pages (same residue, condition, or type): [CEP76 p.Arg568Pro](/variant/cep76-p-arg568pro), [CEP76 p.Lys374=](/variant/cep76-p-lys374), [CEP76 p.Val24Asp](/variant/cep76-p-val24asp), [CEP76 p.His301fs](/variant/cep76-p-his301fs), [CEP76 p.Cys478Arg](/variant/cep76-p-cys478arg), [CEP76 p.Ile101Thr](/variant/cep76-p-ile101thr), [CEP76 p.Leu166Pro](/variant/cep76-p-leu166pro), [CEP76 p.Val265Met](/variant/cep76-p-val265met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 4075828). 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.*