# NM_014679.5(CEP57):c.1125C>T (p.Ser375=)

https://sugi.bio/variant/cep57-p-ser375

## Summary

**CEP57 p.Ser375= (c.1125C>T)** is classified **Likely benign** in CEP57 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CEP57 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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 | [CEP57](https://sugi.bio/atlas/gene/CEP57/) |
| Protein change (HGVS p.) | p.Ser375= |
| Coding change (HGVS c.) | c.1125C>T |
| MANE Select transcript | [NM_014679](https://www.ncbi.nlm.nih.gov/nuccore/NM_014679) |
| Variant type | single nucleotide variant |
| Location | chr11:95828025-95828025 (GRCh38) |
| ClinVar | [VCV4845101](https://www.ncbi.nlm.nih.gov/clinvar/variation/4845101/) |

**All HGVS expressions:** `LRG_526:g.42565C>T`, `LRG_526t1:c.1125C>T`, `NC_000011.10:g.95828025C>T`, `NC_000011.9:g.95561189C>T`, `NG_029829.1:g.42565C>T`, `NM_001243776.2:c.1098C>T`, `NM_001243777.2:c.1047C>T`, `NM_001363604.2:c.1044C>T`, `NM_001440869.1:c.1044C>T`, `NM_001440870.1:c.1044C>T`, `NM_001440871.1:c.1017C>T`, `NM_001440872.1:c.1008C>T`, `NM_001440873.1:c.945C>T`, `NM_001440874.1:c.939C>T`, `NM_001440875.1:c.936C>T`, `NM_001440876.1:c.930C>T`, `NM_001440877.1:c.927C>T`, `NM_001440878.1:c.927C>T`, `NM_001440879.1:c.900C>T`, `NM_001440880.1:c.864C>T`, `NM_001440881.1:c.828C>T`, `NM_001440882.1:c.822C>T`, `NM_014679.5:c.1125C>T`

## Computational & population evidence {#evidence}

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

- **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 2.101, GERP 1.63, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.08**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.64 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.*
- Pangolin: Δ**0.24** (loss), gain 0.03 / loss 0.24. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,364 in the highest group · 1/1,460,246 alleles overall — very rare (popmax 8.48e-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}

**CEP57** population constraint: LOEUF 0.74, pLI 6.8356e-06, missense-Z 0.050453. *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):

- **mosaic variegated aneuploidy syndrome 2** — Definitive (AR)

## Protein context {#protein}

Residue **375** lies in an α-helix; the 'mediates interaction with microtubules' region.

AlphaFold model confidence (whole protein): pLDDT 76.32, 49% of residues very-high.

**3 experimental structure(s)** (PDB): [4L0R](https://www.rcsb.org/structure/4L0R), [8IBH](https://www.rcsb.org/structure/8IBH), [9I7Q](https://www.rcsb.org/structure/9I7Q).

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

*Describes the biological roles of CEP57 (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.*

**How this variant is thought to act:** CEP57's established molecular role includes fibroblast growth factor binding. p.Ser375= falls in the mediates interaction with microtubules region.


### Pathways affected {#pathways}

CEP57 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | 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 |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | other |

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

**Molecular function:** fibroblast growth factor binding, protein homodimerization activity.

**Biological process:** fibroblast growth factor receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CEP57 variant pages (same residue, condition, or type): [CEP57 p.Ser375Arg](/variant/cep57-p-ser375arg), [CEP57 p.Ser375Asn](/variant/cep57-p-ser375asn), [CEP57 p.Ala19Gly](/variant/cep57-p-ala19gly), [CEP57 p.Ala278Thr](/variant/cep57-p-ala278thr), [CEP57 p.Ala412Thr](/variant/cep57-p-ala412thr), [CEP57 p.Ala4Gly](/variant/cep57-p-ala4gly), [CEP57 p.Ala4Val](/variant/cep57-p-ala4val), [CEP57 p.Ala68Val](/variant/cep57-p-ala68val).

### 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 4845101). 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.*