# NM_001142568.3(BBX):c.180C>T (p.Ala60=)

https://sugi.bio/variant/bbx-p-ala60

## Summary

**BBX p.Ala60= (c.180C>T)** is classified **Likely benign** in BBX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-12-08). Rare (popmax 0.314%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs150018279 · 2 submitters · rare (popmax 0.314%, nfe)

## For patients & families {#patients}

This is a change in the BBX gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Ala60= |
| Coding change (HGVS c.) | c.180C>T |
| MANE Select transcript | [NM_001142568](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142568) |
| dbSNP | [rs150018279](https://www.ncbi.nlm.nih.gov/snp/rs150018279/) |
| Variant type | single nucleotide variant |
| Location | chr3:107716624-107716624 (GRCh38) |
| ClinVar | [VCV714946](https://www.ncbi.nlm.nih.gov/clinvar/variation/714946/) |

**All HGVS expressions:** `NC_000003.11:g.107435471C>T`, `NC_000003.12:g.107716624C>T`, `NM_001142568.3:c.180C>T`, `NM_001276286.2:c.180C>T`, `NM_020235.7:c.180C>T`

## 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 -9.555, GERP -4.12 — fast-evolving / accelerated position
- CADD: **PHRED 1.147**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.32 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 **0.314%** (nfe) · FAF95 0.306% · FAF99 0.303% · 3,709/1,179,642 in the highest group · 4,075/1,613,476 alleles overall — rare (popmax 0.314%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.314% | 318 |
| Remaining individuals (not grpmax-eligible) | 0.234% | 428 |
| South Asian | 0.0956% | 1,046 |
| Finnish (not grpmax-eligible) | 0.0703% | 1,422 |
| Middle Eastern | 0.0661% | 1,513 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0608% | 1,643 |
| Admixed American | 0.0517% | 1,935 |
| African / African-American | 0.0467% | 2,142 |

*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 **60** lies in the 'disordered' 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.Ala60= falls in the disordered region.


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

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

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2017-12-08.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-12-08 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related BBX variant pages (same residue, condition, or type): [BBX p.Ala442Thr](/variant/bbx-p-ala442thr), [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), [BBX p.Ala375Thr](/variant/bbx-p-ala375thr), [BBX p.Ala592Thr](/variant/bbx-p-ala592thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 714946). 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.*