# NM_001379291.1(BRD4):c.3693_3709dup (p.Arg1237fs)

https://sugi.bio/variant/brd4-p-arg1237fs

## Summary

**BRD4 p.Arg1237fs (c.3693_3709dup)** is classified **Pathogenic** in BRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). No gnomAD frequency available for this variant; Associated with intellectual disability.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2512703983 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BRD4 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual disability.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 204 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BRD4 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRD4](https://sugi.bio/atlas/gene/BRD4/) |
| Protein change (HGVS p.) | p.Arg1237fs |
| Coding change (HGVS c.) | c.3693_3709dup |
| MANE Select transcript | [NM_001379291](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379291) |
| dbSNP | [rs2512703983](https://www.ncbi.nlm.nih.gov/snp/rs2512703983/) |
| Variant type | Duplication |
| Location | chr19:15239131-15239132 (GRCh38) |
| ClinVar | [VCV1708222](https://www.ncbi.nlm.nih.gov/clinvar/variation/1708222/) |

**All HGVS expressions:** `NC_000019.10:g.15239134_15239150dup`, `NC_000019.9:g.15349945_15349961dup`, `NM_001379291.1:c.3693_3709dup`, `NM_001379291.1:c.3709_3710insTCGGGAGAAAGAGGAGC`, `NM_058243.3:c.3693_3709dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.884, GERP 1.34, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.191, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 20**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**BRD4** population constraint: LOEUF 0.191, pLI 1, missense-Z 2.6425. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **1237** lies in the 'c-terminal (ctd) region' region; the 'disordered' region; a UniProt-annotated variant site (found in a patient with a neurodevelopmental syndrome; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 56.20, 19% of residues very-high.

**613 experimental structure(s)** (PDB): [2I8N](https://www.rcsb.org/structure/2I8N), [2LSP](https://www.rcsb.org/structure/2LSP), [2MJV](https://www.rcsb.org/structure/2MJV), [2N3K](https://www.rcsb.org/structure/2N3K), [2NCZ](https://www.rcsb.org/structure/2NCZ), [2ND0](https://www.rcsb.org/structure/2ND0) — incl. mutant structure 8CKF.

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

*Describes the biological roles of BRD4 (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:** BRD4's established molecular role includes transcription cis-regulatory region binding. p.Arg1237fs falls in the c-terminal (ctd) region region. In Reactome, BRD4 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** BRD4 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

BRD4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |

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

**Molecular function:** transcription cis-regulatory region binding, p53 binding, chromatin binding, transcription coregulator activity, transcription coactivator activity, RNA polymerase II CTD heptapeptide repeat kinase activity.

**Biological process:** chromatin remodeling, regulation of transcription by RNA polymerase II, DNA damage response, positive regulation of G2/M transition of mitotic cell cycle, positive regulation of transcription elongation by RNA polymerase II, positive regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-04 |

## Associated conditions {#conditions}

[intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/).

**Reported phenotype names (ClinVar):** Intellectual disability, intellectual disabilities, Intellectual functioning disability, Intellectual developmental disorder.

## Similar variants {#similar}

Related BRD4 variant pages (same residue, condition, or type): [BRD4 p.Gln256fs](/variant/brd4-p-gln256fs), [BRD4 p.Gln910fs](/variant/brd4-p-gln910fs), [BRD4 p.Glu1225fs](/variant/brd4-p-glu1225fs), [BRD4 p.Leu958fs](/variant/brd4-p-leu958fs), [BRD4 p.Pro47fs](/variant/brd4-p-pro47fs), [BRD4 p.Pro568fs](/variant/brd4-p-pro568fs), [BRD4 p.Val439fs](/variant/brd4-p-val439fs), [BRD4 p.Ala1308_Thr1309insAla](/variant/brd4-p-ala1308-thr1309insala).

### 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 1708222). 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.*