# NM_001379291.1(BRD4):c.1694C>T (p.Ala565Val)

https://sugi.bio/variant/brd4-p-ala565val

## Summary

**BRD4 p.Ala565Val (c.1694C>T)** is classified **Uncertain significance** in BRD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-10). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs971737368 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the BRD4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [BRD4](https://sugi.bio/atlas/gene/BRD4/) |
| Protein change (HGVS p.) | p.Ala565Val |
| Coding change (HGVS c.) | c.1694C>T |
| MANE Select transcript | [NM_001379291](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379291) |
| dbSNP | [rs971737368](https://www.ncbi.nlm.nih.gov/snp/rs971737368/) |
| Variant type | single nucleotide variant |
| Location | chr19:15256121-15256121 (GRCh38) |
| ClinVar | [VCV2352746](https://www.ncbi.nlm.nih.gov/clinvar/variation/2352746/) |

**All HGVS expressions:** `NC_000019.10:g.15256121G>A`, `NC_000019.9:g.15366932G>A`, `NM_001330384.2:c.1694C>T`, `NM_001379291.1:c.1694C>T`, `NM_001379292.1:c.1694C>T`, `NM_014299.3:c.1694C>T`, `NM_058243.3:c.1694C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0703)
- REVEL 0.083 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.426 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.812, GERP 2.29, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.1**. 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 1.09** across the covering region of the MANE Select transcript (15,255,539–15,256,211), spanning 672 bp. Chi-square p 0.42. 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 (G>C, Δ0.31 donor 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 **0.00446%** (eas) · FAF95 0.000738% · FAF99 0.000276% · 2/44,892 in the highest group · 8/1,611,712 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00963% | 10,382 |
| East Asian (grpmax) | 0.00446% | 22,446 |

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.*

## 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 **565** lies in a UniProt-annotated variant site (found in a patient with a neurodevelopmental syndrome; likely pathogenic); the 'disordered' region; the 'bid region' region.

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.Ala565Val falls in the disordered 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related BRD4 variant pages (same residue, condition, or type): [BRD4 p.Ala220Thr](/variant/brd4-p-ala220thr), [BRD4 p.Ala409Thr](/variant/brd4-p-ala409thr), [BRD4 p.Asp497Gly](/variant/brd4-p-asp497gly), [BRD4 p.Gln32Arg](/variant/brd4-p-gln32arg), [BRD4 p.Glu715Lys](/variant/brd4-p-glu715lys), [BRD4 p.Glu718Gln](/variant/brd4-p-glu718gln), [BRD4 p.Gly6Ala](/variant/brd4-p-gly6ala), [BRD4 p.Ile300Val](/variant/brd4-p-ile300val).

### 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 2352746). 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.*