# NM_020183.6(BMAL2):c.352C>T (p.Arg118Trp)

https://sugi.bio/variant/bmal2-p-arg118trp

## Summary

**BMAL2 p.Arg118Trp (c.352C>T)** is classified **Uncertain significance** in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.505); Very rare (popmax 0.00878%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs140062821 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00878%, sas)

## 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.Arg118Trp |
| Coding change (HGVS c.) | c.352C>T |
| MANE Select transcript | [NM_020183](https://www.ncbi.nlm.nih.gov/nuccore/NM_020183) |
| dbSNP | [rs140062821](https://www.ncbi.nlm.nih.gov/snp/rs140062821/) |
| Variant type | single nucleotide variant |
| Location | chr12:27380272-27380272 (GRCh38) |
| ClinVar | [VCV2521509](https://www.ncbi.nlm.nih.gov/clinvar/variation/2521509/) |

**All HGVS expressions:** `NC_000012.11:g.27533205C>T`, `NC_000012.12:g.27380272C>T`, `NG_030359.2:g.52419C>T`, `NM_001248002.3:c.310C>T`, `NM_001248003.3:c.241C>T`, `NM_001248004.3:c.208C>T`, `NM_001248005.3:c.241C>T`, `NM_001394524.1:c.385C>T`, `NM_001394525.1:c.343C>T`, `NM_001394526.1:c.250C>T`, `NM_001394527.1:c.208C>T`, `NM_001394528.1:c.241C>T`, `NM_001394529.1:c.208C>T`, `NM_020183.6:c.352C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.505) — no call either way
- REVEL 0.772 (pathogenic-leaning)
- SaProt LLR -12.798 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 2.687, GERP -3.87, phastCons 1 — highly conserved
- CADD: **PHRED 25.5**. 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>G, Δ0.25 acceptor loss), 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 **0.00878%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/91,066 in the highest group · 49/1,614,022 alleles overall — very rare (popmax 0.00878%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00878% | 11,383 |
| European (non-Finnish) | 0.00331% | 30,255 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |

*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}

Residue **118** lies in the bhlh domain; the 'interaction with per2' region.

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. p.Arg118Trp falls in the bhlh domain.


### 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 2025-08-09.

**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 | 2025-08-09 |

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

## Similar variants {#similar}

Related BMAL2 variant pages (same residue, condition, or type): [BMAL2 p.Arg118Gln](/variant/bmal2-p-arg118gln), [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.Arg142His](/variant/bmal2-p-arg142his), [BMAL2 p.Arg173Ile](/variant/bmal2-p-arg173ile), [BMAL2 p.Arg273Cys](/variant/bmal2-p-arg273cys).

### 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 2521509). 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.*