# NM_020183.6(BMAL2):c.853C>T (p.Arg285Trp)

https://sugi.bio/variant/bmal2-p-arg285trp

## Summary

**BMAL2 p.Arg285Trp (c.853C>T)** is classified **Uncertain significance** in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.8067); Ultra-rare (popmax 0.0149%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs141432546 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0149%, nfe)

## For patients & families {#patients}

This is a change in the BMAL2 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 | [BMAL2](https://sugi.bio/atlas/gene/BMAL2/) |
| Protein change (HGVS p.) | p.Arg285Trp |
| Coding change (HGVS c.) | c.853C>T |
| MANE Select transcript | [NM_020183](https://www.ncbi.nlm.nih.gov/nuccore/NM_020183) |
| dbSNP | [rs141432546](https://www.ncbi.nlm.nih.gov/snp/rs141432546/) |
| Variant type | single nucleotide variant |
| Location | chr12:27390173-27390173 (GRCh38) |
| ClinVar | [VCV3134483](https://www.ncbi.nlm.nih.gov/clinvar/variation/3134483/) |

**All HGVS expressions:** `NC_000012.11:g.27543106C>T`, `NC_000012.12:g.27390173C>T`, `NG_030359.2:g.62320C>T`, `NM_001248002.3:c.811C>T`, `NM_001248003.3:c.742C>T`, `NM_001248004.3:c.709C>T`, `NM_001248005.3:c.742C>T`, `NM_001394524.1:c.886C>T`, `NM_001394525.1:c.844C>T`, `NM_001394526.1:c.751C>T`, `NM_001394527.1:c.709C>T`, `NM_001394528.1:c.649C>T`, `NM_001394529.1:c.616C>T`, `NM_020183.6:c.853C>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** (0.8067)
- REVEL 0.41 (indeterminate)
- SaProt LLR -13.485 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 2.218, GERP 0.796, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in BMAL2 (of 3,708 modeled).
- CADD: **PHRED 24.6**. 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 0.92** across the covering region of the MANE Select transcript (27,333,073–27,420,529), spanning 87,456 bp. Chi-square p 0.025. 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, Δ0.58 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 **0.0149%** (nfe) · FAF95 0.0131% · FAF99 0.0124% · 176/1,179,684 in the highest group · 191/1,613,624 alleles overall — ultra-rare (popmax 0.0149%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,208 |
| European (non-Finnish) (grpmax) | 0.0149% | 6,703 |
| African / African-American | 0.00267% | 37,494 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,994 |

Remaining individuals 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 61.96, 29% of residues very-high.

**1 experimental structure(s)** (PDB): [2KDK](https://www.rcsb.org/structure/2KDK).

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

*Describes the biological roles of BMAL2 (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:** BMAL2's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

BMAL2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | curated |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, E-box binding.

**Biological process:** regulation of transcription by RNA polymerase II, circadian rhythm, circadian regulation of gene expression, positive regulation of circadian rhythm, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-08.

**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 | 2024-10-08 |

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

## Similar variants {#similar}

Related BMAL2 variant pages (same residue, condition, or type): [BMAL2 p.Ala141Val](/variant/bmal2-p-ala141val), [BMAL2 p.Ala388Thr](/variant/bmal2-p-ala388thr), [BMAL2 p.Ala3Thr](/variant/bmal2-p-ala3thr), [BMAL2 p.Ala583Thr](/variant/bmal2-p-ala583thr), [BMAL2 p.Arg118Gln](/variant/bmal2-p-arg118gln), [BMAL2 p.Arg118Trp](/variant/bmal2-p-arg118trp), [BMAL2 p.Arg142His](/variant/bmal2-p-arg142his), [BMAL2 p.Arg173Ile](/variant/bmal2-p-arg173ile).

### 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 3134483). 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.*