# NM_001379291.1(BRD4):c.1224delinsCA (p.Glu408fs)

https://sugi.bio/variant/brd4-p-glu408fs

## Summary

**BRD4 p.Glu408fs (c.1224delinsCA)** is classified **Pathogenic** in BRD4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-25). No gnomAD frequency available for this variant; Associated with Cornelia de Lange syndrome 6.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2512580369 · 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 Cornelia de Lange syndrome 6.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026892/index) · [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.Glu408fs |
| Coding change (HGVS c.) | c.1224delinsCA |
| MANE Select transcript | [NM_001379291](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379291) |
| dbSNP | [rs2512580369](https://www.ncbi.nlm.nih.gov/snp/rs2512580369/) |
| Variant type | Indel |
| Location | chr19:15263537-15263537 (GRCh38) |
| ClinVar | [VCV2671881](https://www.ncbi.nlm.nih.gov/clinvar/variation/2671881/) |

**All HGVS expressions:** `NC_000019.10:g.15263537delinsTG`, `NC_000019.9:g.15374348delinsTG`, `NM_001330384.2:c.1224delinsCA`, `NM_001379291.1:c.1224delinsCA`, `NM_001379292.1:c.1224delinsCA`, `NM_014299.3:c.1224delinsCA`, `NM_058243.3:c.1224delinsCA`

## 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 2.692, GERP 2.58, 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 7 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 indel 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 **408** lies in an α-helix; the bromo 2 domain; 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.Glu408fs falls in the bromo 2 domain. 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-01-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2024-01-25 |

## Associated conditions {#conditions}

[Cornelia de Lange syndrome 6](https://sugi.bio/atlas/disease/cornelia-de-lange-syndrome-6/).

**Reported phenotype names (ClinVar):** Cornelia de Lange syndrome 6.

## Similar variants {#similar}

Related BRD4 variant pages (same residue, condition, or type): [BRD4 p.Gln256fs](/variant/brd4-p-gln256fs), [BRD4 p.Tyr430Cys](/variant/brd4-p-tyr430cys), [BRD4 p.Thr295Pro](/variant/brd4-p-thr295pro), [BRD4 c.1552-1G>A](/variant/brd4-c-1552-minus-1g-a), [BRD4 c.2211+2T>C](/variant/brd4-c-2211-plus-2t-c), [BRD4 c.285+1G>T](/variant/brd4-c-285-plus-1g-t), [BRD4 p.Gln1105fs](/variant/brd4-p-gln1105fs), [BRD4 p.Gln910fs](/variant/brd4-p-gln910fs).

### 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 2671881). 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.*