# NM_001353108.3(CEP63):c.406C>T (p.Arg136Trp)

https://sugi.bio/variant/cep63-p-arg136trp

## Summary

**CEP63 p.Arg136Trp (c.406C>T)** is classified **Uncertain significance** in CEP63 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.1205); Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00669%, eas)

## For patients & families {#patients}

This is a change in the CEP63 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CEP63](https://sugi.bio/atlas/gene/CEP63/) |
| Protein change (HGVS p.) | p.Arg136Trp |
| Coding change (HGVS c.) | c.406C>T |
| MANE Select transcript | [NM_001353108](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353108) |
| Variant type | single nucleotide variant |
| Location | chr3:134532865-134532865 (GRCh38) |
| ClinVar | [VCV4001106](https://www.ncbi.nlm.nih.gov/clinvar/variation/4001106/) |

**All HGVS expressions:** `NC_000003.11:g.134251707C>T`, `NC_000003.12:g.134532865C>T`, `NG_032870.1:g.52133C>T`, `NG_032870.2:g.52143C>T`, `NM_001042383.2:c.406C>T`, `NM_001042384.2:c.406C>T`, `NM_001042400.3:c.406C>T`, `NM_001353108.3:c.406C>T`, `NM_001353109.1:c.406C>T`, `NM_001353110.1:c.406C>T`, `NM_001353111.2:c.406C>T`, `NM_001353112.2:c.406C>T`, `NM_001353113.1:c.406C>T`, `NM_001353117.2:c.406C>T`, `NM_001353118.1:c.433C>T`, `NM_001353119.2:c.406C>T`, `NM_001353120.2:c.406C>T`, `NM_001353121.2:c.406C>T`, `NM_001353122.1:c.406C>T`, `NM_001353123.2:c.406C>T`, `NM_001353124.2:c.406C>T`, `NM_001353125.2:c.322C>T`, `NM_001353126.2:c.43C>T`, `NM_025180.5:c.406C>T`, `NR_148352.2:n.931C>T`, `NR_148353.2:n.931C>T`, `NR_148354.2:n.931C>T`, `NR_148355.1:n.760C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1205)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.914 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.251, GERP 1.75, phastCons 0.69 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.7**. 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 1.03** across the covering region of the MANE Select transcript (134,495,321–134,561,532), spanning 66,211 bp. Chi-square p 0.39. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.22** (loss), gain 0.00 / loss 0.22. Agrees with SpliceAI. 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 **0.00669%** (eas) · FAF95 0.00178% · FAF99 0.000892% · 3/44,830 in the highest group · 15/1,461,432 alleles overall — very rare (popmax 0.00669%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00669% | 14,943 |
| Admixed American | 0.00167% | 60,008 |
| South Asian | 0.0011% | 91,070 |
| European (non-Finnish) | 0.000848% | 117,978 |

*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}

**CEP63** population constraint: LOEUF 1.127, pLI 2.2922e-17, missense-Z -0.15809. *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 77.95, 59% of residues very-high.

**4 experimental structure(s)** (PDB): [6CSU](https://www.rcsb.org/structure/6CSU), [6CSV](https://www.rcsb.org/structure/6CSV), [7W91](https://www.rcsb.org/structure/7W91), [9I7Q](https://www.rcsb.org/structure/9I7Q).

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

*Describes the biological roles of CEP63 (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:** CEP63's established molecular role includes molecular adaptor activity.


### Pathways affected {#pathways}

CEP63 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}

**Molecular function:** molecular adaptor activity.

**Biological process:** centriole replication, negative regulation of innate immune response, protein stabilization, negative regulation of protein K63-linked ubiquitination.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-18 |

## 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 CEP63 variant pages (same residue, condition, or type): [CEP63 p.Arg215Trp](/variant/cep63-p-arg215trp), [CEP63 p.Arg46His](/variant/cep63-p-arg46his), [CEP63 p.Arg474His](/variant/cep63-p-arg474his), [CEP63 p.Arg57His](/variant/cep63-p-arg57his), [CEP63 p.Asn301Ile](/variant/cep63-p-asn301ile), [CEP63 p.Asn633Asp](/variant/cep63-p-asn633asp), [CEP63 p.Asn633Ser](/variant/cep63-p-asn633ser), [CEP63 p.Gln645Glu](/variant/cep63-p-gln645glu).

### 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 4001106). 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.*