# NM_014984.4(CEP131):c.2374C>T (p.Arg792Trp)

https://sugi.bio/variant/cep131-p-arg792trp

## Summary

**CEP131 p.Arg792Trp (c.2374C>T)** is classified **Uncertain significance** in CEP131 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-18). AlphaMissense: likely benign (0.2052); Very rare (popmax 0.00334%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00334%, amr)

## For patients & families {#patients}

This is a change in the CEP131 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CEP131](https://sugi.bio/atlas/gene/CEP131/) |
| Protein change (HGVS p.) | p.Arg792Trp |
| Coding change (HGVS c.) | c.2374C>T |
| MANE Select transcript | [NM_014984](https://www.ncbi.nlm.nih.gov/nuccore/NM_014984) |
| Variant type | single nucleotide variant |
| Location | chr17:81192791-81192791 (GRCh38) |
| ClinVar | [VCV4652254](https://www.ncbi.nlm.nih.gov/clinvar/variation/4652254/) |

**All HGVS expressions:** `NC_000017.10:g.79166591G>A`, `NC_000017.11:g.81192791G>A`, `NM_001009811.4:c.2322-198C>T`, `NM_001319228.2:c.2383C>T`, `NM_001319229.2:c.2331-198C>T`, `NM_014984.4:c.2374C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2052)
- REVEL 0.176 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.246 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 1.242, GERP -0.335, phastCons 0.761 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R795W** vs ClinVar **R792W**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 22.4**. 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 1.06** across the covering region of the MANE Select transcript (81,189,772–81,199,480), spanning 9,708 bp. Chi-square p 0.047. 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, Δ0.30 donor loss), 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 **0.00334%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,962 in the highest group · 6/1,597,654 alleles overall — very rare (popmax 0.00334%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00334% | 29,981 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,186 |
| European (non-Finnish) | 0.000255% | 392,906 |

*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}

**CEP131** population constraint: LOEUF 1.031, pLI 1.6277e-28, missense-Z -0.88157. *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 67.20, 33% of residues very-high.

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

*Describes the biological roles of CEP131 (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:** CEP131's established molecular role includes protein homodimerization activity.


### Pathways affected {#pathways}

CEP131 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:** protein homodimerization activity, protein-containing complex binding.

**Biological process:** positive regulation of cell population proliferation, regulation of centrosome duplication, intraciliary transport involved in cilium assembly, protein localization to centrosome, positive regulation of intracellular protein transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-18.

**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 | 2025-09-18 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CEP131 variant pages (same residue, condition, or type): [CEP131 p.Arg792Gln](/variant/cep131-p-arg792gln), [CEP131 p.Pro365Ser](/variant/cep131-p-pro365ser), [CEP131 p.Ala1024Thr](/variant/cep131-p-ala1024thr), [CEP131 p.Ala1042Ser](/variant/cep131-p-ala1042ser), [CEP131 p.Ala113Pro](/variant/cep131-p-ala113pro), [CEP131 p.Ala271Pro](/variant/cep131-p-ala271pro), [CEP131 p.Ala332Ser](/variant/cep131-p-ala332ser), [CEP131 p.Ala403Val](/variant/cep131-p-ala403val).

### 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 4652254). 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.*