# NM_001379291.1(BRD4):c.20C>G (p.Pro7Arg)

https://sugi.bio/variant/brd4-p-pro7arg

## Summary

**BRD4 p.Pro7Arg (c.20C>G)** is classified **Uncertain significance** in BRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-09). AlphaMissense: ambiguous (0.3451); Very rare (popmax 0.00426%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1415180178 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00426%, nfe)

## 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 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 | [BRD4](https://sugi.bio/atlas/gene/BRD4/) |
| Protein change (HGVS p.) | p.Pro7Arg |
| Coding change (HGVS c.) | c.20C>G |
| MANE Select transcript | [NM_001379291](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379291) |
| dbSNP | [rs1415180178](https://www.ncbi.nlm.nih.gov/snp/rs1415180178/) |
| Variant type | single nucleotide variant |
| Location | chr19:15273080-15273080 (GRCh38) |
| ClinVar | [VCV2172528](https://www.ncbi.nlm.nih.gov/clinvar/variation/2172528/) |

**All HGVS expressions:** `NC_000019.10:g.15273080G>C`, `NC_000019.9:g.15383891G>C`, `NM_001330384.2:c.20C>G`, `NM_001379291.1:c.20C>G`, `NM_001379292.1:c.20C>G`, `NM_014299.3:c.20C>G`, `NM_058243.3:c.20C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.3451) — no call either way
- REVEL 0.252 (benign-leaning)
- SaProt LLR -5.804 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 11.717, GERP 2.58, phastCons 1 — highly conserved
- CADD: **PHRED 25.2**. 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 1.00** across the covering region of the MANE Select transcript (15,272,939–15,273,099), spanning 160 bp. Chi-square p 0.98. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00426%** (nfe) · FAF95 0.00328% · FAF99 0.00296% · 50/1,172,942 in the highest group · 52/1,601,974 alleles overall — very rare (popmax 0.00426%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00426% | 23,459 |
| African / African-American | 0.00268% | 37,358 |

*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 **7** lies in the 'disordered' 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.Pro7Arg 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-09 |

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

## Similar variants {#similar}

Related BRD4 variant pages (same residue, condition, or type): [BRD4 p.Tyr430Cys](/variant/brd4-p-tyr430cys), [BRD4 p.Ala220Thr](/variant/brd4-p-ala220thr), [BRD4 p.Ala409Thr](/variant/brd4-p-ala409thr), [BRD4 p.Ala565Val](/variant/brd4-p-ala565val), [BRD4 p.Asp337Asn](/variant/brd4-p-asp337asn), [BRD4 p.Asp497Gly](/variant/brd4-p-asp497gly), [BRD4 p.Gln32Arg](/variant/brd4-p-gln32arg), [BRD4 p.Glu1123Lys](/variant/brd4-p-glu1123lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2172528). 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.*