# NM_012179.4(FBXO7):c.122+245G>A

https://sugi.bio/variant/fbxo7-c-122-plus-245g-a

## Summary

**FBXO7 c.122+245G>A** is classified **Likely benign** in FBXO7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-18). Rare (popmax 0.664%, afr); Associated with FBXO7-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs199636063 · 1 submitter · 1 linked condition · rare (popmax 0.664%, afr)

## For patients & families {#patients}

This is a change in the FBXO7 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to FBXO7-related disorder.

*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 | [FBXO7](https://sugi.bio/atlas/gene/FBXO7/) |
| Coding change (HGVS c.) | c.122+245G>A |
| MANE Select transcript | [NM_012179](https://www.ncbi.nlm.nih.gov/nuccore/NM_012179) |
| dbSNP | [rs199636063](https://www.ncbi.nlm.nih.gov/snp/rs199636063/) |
| Variant type | single nucleotide variant |
| Location | chr22:32475369-32475369 (GRCh38) |
| ClinVar | [VCV3033374](https://www.ncbi.nlm.nih.gov/clinvar/variation/3033374/) |

**All HGVS expressions:** `NC_000022.10:g.32871356G>A`, `NC_000022.11:g.32475369G>A`, `NG_016001.2:g.5650G>A`, `NG_145487.1:g.398G>A`, `NM_001033024.2:c.8G>A`, `NM_001257990.2:c.-250G>A`, `NM_012179.4:c.122+245G>A`

## Computational & population evidence {#evidence}

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

- **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 0.025, GERP -4.1 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.763**. 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.*
- Splice region: **deep intronic (+245 nt into the intron)**.
- 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 **0.664%** (afr) · FAF95 0.615% · FAF99 0.596% · 495/74,570 in the highest group · 534/1,610,344 alleles overall — rare (popmax 0.664%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.664% | 151 |
| Remaining individuals (not grpmax-eligible) | 0.0305% | 3,283 |
| Admixed American | 0.0217% | 4,600 |
| South Asian | 0.00221% | 45,284 |
| European (non-Finnish) | 0.000424% | 235,743 |

*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}


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.


### 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-06-18.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-18 |

## Associated conditions {#conditions}

[FBXO7-related disorder](https://sugi.bio/atlas/disease/fbxo7-related-disorder/).

**Reported phenotype names (ClinVar):** FBXO7-related disorder, FBXO7-related condition.

## Similar variants {#similar}

Related FBXO7 variant pages (same residue, condition, or type): [FBXO7 p.Thr44Asn](/variant/fbxo7-p-thr44asn), [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).

### 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 3033374). 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.*