# NM_012179.4(FBXO7):c.155A>G (p.Tyr52Cys)

https://sugi.bio/variant/fbxo7-p-tyr52cys

## Summary

**FBXO7 p.Tyr52Cys (c.155A>G)** is classified **Likely benign** in FBXO7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0683); Rare (popmax 0.343%, eas); Associated with parkinsonian-pyramidal syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs550610502 · 3 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.343%, eas)

## For patients & families {#patients}

This is a change in the FBXO7 gene that is classified as likely benign — not considered 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.Tyr52Cys |
| Coding change (HGVS c.) | c.155A>G |
| MANE Select transcript | [NM_012179](https://www.ncbi.nlm.nih.gov/nuccore/NM_012179) |
| dbSNP | [rs550610502](https://www.ncbi.nlm.nih.gov/snp/rs550610502/) |
| Variant type | single nucleotide variant |
| Location | chr22:32479013-32479013 (GRCh38) |
| ClinVar | [VCV901597](https://www.ncbi.nlm.nih.gov/clinvar/variation/901597/) |

**All HGVS expressions:** `NC_000022.10:g.32875000A>G`, `NC_000022.11:g.32479013A>G`, `NG_016001.2:g.9294A>G`, `NM_001033024.2:c.38-120A>G`, `NM_001257990.2:c.-188A>G`, `NM_012179.4:c.155A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0683)
- REVEL 0.059 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.974 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.053, GERP 1.61, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.343%** (eas) · FAF95 0.299% · FAF99 0.282% · 154/44,884 in the highest group · 227/1,614,228 alleles overall — rare (popmax 0.343%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.343% | 291 |
| South Asian | 0.0428% | 2,336 |
| Remaining individuals (not grpmax-eligible) | 0.024% | 4,167 |
| African / African-American | 0.00533% | 18,765 |
| Admixed American | 0.00333% | 30,016 |
| European (non-Finnish) | 0.0011% | 90,771 |

*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 **52** lies in the 'ubiquitin-like' 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.Tyr52Cys falls in the ubiquitin-like 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-08 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **52** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FBXO7 p.Tyr52Ter](/variant/fbxo7-p-tyr52ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FBXO7 variant pages (same residue, condition, or type): [FBXO7 p.Tyr52Ter](/variant/fbxo7-p-tyr52ter), [FBXO7 p.Tyr52=](/variant/fbxo7-p-tyr52), [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).

### 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 901597). 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.*