# NM_032142.4(CEP192):c.6592T>C (p.Ser2198Pro)

https://sugi.bio/variant/cep192-p-ser2198pro

## Summary

**CEP192 p.Ser2198Pro (c.6592T>C)** is classified **Uncertain significance** in CEP192 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1975); Very rare (popmax 0.000938%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000938%, nfe)

## For patients & families {#patients}

This is a change in the CEP192 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 | [CEP192](https://sugi.bio/atlas/gene/CEP192/) |
| Protein change (HGVS p.) | p.Ser2198Pro |
| Coding change (HGVS c.) | c.6592T>C |
| MANE Select transcript | [NM_032142](https://www.ncbi.nlm.nih.gov/nuccore/NM_032142) |
| Variant type | single nucleotide variant |
| Location | chr18:13099510-13099510 (GRCh38) |
| ClinVar | [VCV3266112](https://www.ncbi.nlm.nih.gov/clinvar/variation/3266112/) |

**All HGVS expressions:** `NC_000018.10:g.13099510T>C`, `NC_000018.9:g.13099509T>C`, `NM_032142.4:c.6592T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1975)
- REVEL 0.263 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.298 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.146, GERP 2.22, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.6**. 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 0.96** across the covering region of the MANE Select transcript (12,999,425–13,124,767), spanning 125,342 bp. Chi-square p 0.044. 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 (T>G, Δ0.20 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.*
- Pangolin: Δ**0.25** (loss), gain 0.00 / loss 0.25. 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 **0.000938%** (nfe) · FAF95 0.000503% · FAF99 0.000368% · 11/1,173,036 in the highest group · 11/1,448,164 alleles overall — very rare (popmax 0.000938%, 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}

**CEP192** population constraint: LOEUF 0.61, pLI 3.2978e-11, missense-Z 1.622. *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 51.37, 2% of residues very-high.

**6 experimental structure(s)** (PDB): [4N7Z](https://www.rcsb.org/structure/4N7Z), [6FVI](https://www.rcsb.org/structure/6FVI), [6W3J](https://www.rcsb.org/structure/6W3J), [7PTB](https://www.rcsb.org/structure/7PTB), [8GUW](https://www.rcsb.org/structure/8GUW), [8PR7](https://www.rcsb.org/structure/8PR7).

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

*Describes the biological roles of CEP192 (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:** CEP192's established molecular role includes phosphatase binding.


### Pathways affected {#pathways}

CEP192 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:** phosphatase binding.

**Biological process:** protein localization to centrosome, centrosome-templated microtubule nucleation, mitotic spindle assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-29.

**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 | 2024-04-29 |

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

## Similar variants {#similar}

Related CEP192 variant pages (same residue, condition, or type): [CEP192 p.Ala2312Val](/variant/cep192-p-ala2312val), [CEP192 p.Gly37Val](/variant/cep192-p-gly37val), [CEP192 p.Asn1883Ser](/variant/cep192-p-asn1883ser), [CEP192 p.Gly1571=](/variant/cep192-p-gly1571), [CEP192 p.Leu111Phe](/variant/cep192-p-leu111phe), [CEP192 p.Pro1159Arg](/variant/cep192-p-pro1159arg), [CEP192 p.Pro613=](/variant/cep192-p-pro613), [CEP192 p.Thr1053Ala](/variant/cep192-p-thr1053ala).

### 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 3266112). 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.*