# NM_012179.4(FBXO7):c.274G>C (p.Asp92His)

https://sugi.bio/variant/fbxo7-p-asp92his

## Summary

**FBXO7 p.Asp92His (c.274G>C)** is classified **Uncertain significance** in FBXO7 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.2278); Ultra-rare (popmax 0.0791%, sas); Associated with parkinsonian-pyramidal syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs139135860 · 5 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0791%, sas)

## For patients & families {#patients}

This is a change in the FBXO7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 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.Asp92His |
| Coding change (HGVS c.) | c.274G>C |
| MANE Select transcript | [NM_012179](https://www.ncbi.nlm.nih.gov/nuccore/NM_012179) |
| dbSNP | [rs139135860](https://www.ncbi.nlm.nih.gov/snp/rs139135860/) |
| Variant type | single nucleotide variant |
| Location | chr22:32479132-32479132 (GRCh38) |
| ClinVar | [VCV341308](https://www.ncbi.nlm.nih.gov/clinvar/variation/341308/) |

**All HGVS expressions:** `NC_000022.10:g.32875119G>C`, `NC_000022.11:g.32479132G>C`, `NG_016001.2:g.9413G>C`, `NM_001033024.2:c.38-1G>C`, `NM_001257990.2:c.-69G>C`, `NM_012179.4:c.274G>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** (0.2278)
- REVEL 0.158 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.517 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.903, GERP 2.53, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.1**. 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 (32,475,003–32,498,527), spanning 23,524 bp. Chi-square p 0.42. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.37**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.37**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0791%** (sas) · FAF95 0.0643% · FAF99 0.0589% · 72/91,080 in the highest group · 244/1,614,020 alleles overall — ultra-rare (popmax 0.0791%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0791% | 1,265 |
| Finnish (not grpmax-eligible) | 0.039% | 2,561 |
| Middle Eastern | 0.0164% | 6,084 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,811 |
| European (non-Finnish) | 0.0114% | 8,806 |
| African / African-American | 0.00401% | 24,965 |
| Admixed American | 0.00167% | 59,994 |

*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 **92** lies in the 'disordered' region; the 'important for interaction with pink1' 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.Asp92His falls in the disordered 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-24 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-01 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Parkinsonian-pyramidal syndrome, not provided, Familial cancer of breast, none provided, PALLIDOPYRAMIDAL SYNDROME, PARKINSON DISEASE 15, AUTOSOMAL RECESSIVE, PARKINSON DISEASE 15, AUTOSOMAL RECESSIVE EARLY-ONSET.

## Similar variants {#similar}

Related FBXO7 variant pages (same residue, condition, or type): [FBXO7 p.Arg321Ter](/variant/fbxo7-p-arg321ter), [FBXO7 p.Arg345Ter](/variant/fbxo7-p-arg345ter), [FBXO7 p.Arg381Ter](/variant/fbxo7-p-arg381ter), [FBXO7 p.Arg45Ter](/variant/fbxo7-p-arg45ter), [FBXO7 p.Arg498Ter](/variant/fbxo7-p-arg498ter), [FBXO7 p.Gln237Ter](/variant/fbxo7-p-gln237ter), [FBXO7 p.Thr22Met](/variant/fbxo7-p-thr22met), [FBXO7 p.Ala84Val](/variant/fbxo7-p-ala84val).

### 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 341308). 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.*