# NM_001142568.3(BBX):c.283C>T (p.Arg95Cys)

https://sugi.bio/variant/bbx-p-arg95cys

## Summary

**BBX p.Arg95Cys (c.283C>T)** is classified **Uncertain significance** in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the BBX 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 | [BBX](https://sugi.bio/atlas/gene/BBX/) |
| Protein change (HGVS p.) | p.Arg95Cys |
| Coding change (HGVS c.) | c.283C>T |
| MANE Select transcript | [NM_001142568](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142568) |
| Variant type | single nucleotide variant |
| Location | chr3:107716727-107716727 (GRCh38) |
| ClinVar | [VCV3260555](https://www.ncbi.nlm.nih.gov/clinvar/variation/3260555/) |

**All HGVS expressions:** `NC_000003.11:g.107435574C>T`, `NC_000003.12:g.107716727C>T`, `NM_001142568.3:c.283C>T`, `NM_001276286.2:c.283C>T`, `NM_020235.7:c.283C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9991)
- REVEL 0.971 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.412 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.699, GERP 2.22, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in BBX (of 5,532 modeled).
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (107,710,461–107,728,926), spanning 18,465 bp. Chi-square p 0.86. 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 (C>A, 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,796 in the highest group · 4/1,461,554 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00312% | 32,017 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,897 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**BBX** population constraint: LOEUF 0.359, pLI 1, missense-Z 1.7997. *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 **95** lies in a DNA-binding region.

AlphaFold model confidence (whole protein): pLDDT 50.79, 8% of residues very-high.

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

*Describes the biological roles of BBX (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:** BBX's established molecular role includes sequence-specific double-stranded DNA binding. p.Arg95Cys falls in a DNA-binding region.


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

**Molecular function:** sequence-specific double-stranded DNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-28.

**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 | 2024-03-28 |

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

## Similar variants {#similar}

Related BBX variant pages (same residue, condition, or type): [BBX p.Arg95His](/variant/bbx-p-arg95his), [BBX p.Ala442Thr](/variant/bbx-p-ala442thr), [BBX p.Ala60=](/variant/bbx-p-ala60), [BBX p.Ala892=](/variant/bbx-p-ala892), [BBX p.Ala139Thr](/variant/bbx-p-ala139thr), [BBX p.Ala143Gly](/variant/bbx-p-ala143gly), [BBX p.Ala269Pro](/variant/bbx-p-ala269pro), [BBX p.Ala354Thr](/variant/bbx-p-ala354thr).

### 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 3260555). 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.*