# NM_012179.4(FBXO7):c.726_727del (p.Cys243fs)

https://sugi.bio/variant/fbxo7-p-cys243fs

## Summary

**FBXO7 p.Cys243fs (c.726_727del)** is classified **Pathogenic/Likely pathogenic** in FBXO7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-17). Very rare (popmax 0.0022%, nfe); Associated with parkinsonian-pyramidal syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1290655316 · 3 submitters · 1 linked condition · very rare (popmax 0.0022%, nfe)

## For patients & families {#patients}

This is a change in the FBXO7 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to parkinsonian-pyramidal syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult |
| Diagnostic panels | FBXO7 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Parkinsonian-pyramidal syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Parkinsonism — Obligate (100%)
- Abnormal pyramidal sign — Obligate (100%)
- Neurogenic bladder — Frequent (79-30%)
- Hypomimic face — Frequent (79-30%)
- Slow saccadic eye movements — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Dystonia — Frequent (79-30%)
- Myoclonus — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009175/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FBXO7](https://sugi.bio/atlas/gene/FBXO7/) |
| Protein change (HGVS p.) | p.Cys243fs |
| Coding change (HGVS c.) | c.726_727del |
| MANE Select transcript | [NM_012179](https://www.ncbi.nlm.nih.gov/nuccore/NM_012179) |
| dbSNP | [rs1290655316](https://www.ncbi.nlm.nih.gov/snp/rs1290655316/) |
| Variant type | Microsatellite |
| Location | chr22:32485144-32485145 (GRCh38) |
| ClinVar | [VCV631890](https://www.ncbi.nlm.nih.gov/clinvar/variation/631890/) |

**All HGVS expressions:** `NC_000022.10:g.32881131CT[2]`, `NC_000022.11:g.32485144CT[2]`, `NG_016001.2:g.15425CT[2]`, `NM_001033024.2:c.489_490del`, `NM_001257990.2:c.384_385del`, `NM_012179.4:c.726_727del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.662, GERP 2.48, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.955, pLI 2.9822e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (nfe) · FAF95 0.00153% · FAF99 0.0013% · 26/1,180,038 in the highest group · 26/1,614,050 alleles overall — very rare (popmax 0.0022%, 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}

**FBXO7** population constraint: LOEUF 0.955, pLI 2.9822e-07, missense-Z -0.0088092; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **243** lies in an α-helix; the 'important for dimerization and interaction with psmf1' region.

AlphaFold model confidence (whole protein): pLDDT 67.13, 13% of residues very-high.

**2 experimental structure(s)** (PDB): [4L9C](https://www.rcsb.org/structure/4L9C), [4L9H](https://www.rcsb.org/structure/4L9H).

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

*Describes the biological roles of FBXO7 (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:** FBXO7's established molecular role includes protein kinase binding. p.Cys243fs falls in the important for dimerization and interaction with psmf1 region.


### Pathways affected {#pathways}

FBXO7 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

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

**Molecular function:** protein kinase binding, ubiquitin protein ligase binding, ubiquitin binding, protein heterodimerization activity, ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** autophagy of mitochondrion, ubiquitin-dependent protein catabolic process, obsolete protein targeting to mitochondrion, regulation of neuron projection development, protein ubiquitination, SCF-dependent proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-17.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-29 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-17 |

## Associated conditions {#conditions}

[parkinsonian-pyramidal syndrome](https://sugi.bio/atlas/disease/parkinsonian-pyramidal-syndrome/).

**Reported phenotype names (ClinVar):** Parkinsonian-pyramidal syndrome, not provided, FBXO7-related disorder, PALLIDOPYRAMIDAL SYNDROME, PARKINSON DISEASE 15, AUTOSOMAL RECESSIVE, PARKINSON DISEASE 15, AUTOSOMAL RECESSIVE EARLY-ONSET, FBXO7-related condition, none provided.

## Similar variants {#similar}

Related FBXO7 variant pages (same residue, condition, or type): [FBXO7 p.Cys243=](/variant/fbxo7-p-cys243), [FBXO7 p.Tyr425fs](/variant/fbxo7-p-tyr425fs), [FBXO7 p.Arg306fs](/variant/fbxo7-p-arg306fs), [FBXO7 p.Leu250fs](/variant/fbxo7-p-leu250fs), [FBXO7 p.Ser189fs](/variant/fbxo7-p-ser189fs), [FBXO7 p.Val274fs](/variant/fbxo7-p-val274fs), [FBXO7 c.1181_1182+1del](/variant/fbxo7-c-1181-1182-plus-1del), [FBXO7 p.Cys243Ser](/variant/fbxo7-p-cys243ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 631890). 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.*