# NM_001379291.1(BRD4):c.3036G>A (p.Pro1012=)

https://sugi.bio/variant/brd4-p-pro1012

## Summary

**BRD4 p.Pro1012= (c.3036G>A)** is classified **Likely benign** in BRD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). Ultra-rare (popmax 0.0456%, sas).

**At a glance:** Likely benign · review: Multiple submitters · 2 submitters · ultra-rare (popmax 0.0456%, sas)

## For patients & families {#patients}

This is a change in the BRD4 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Pro1012= |
| Coding change (HGVS c.) | c.3036G>A |
| MANE Select transcript | [NM_001379291](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379291) |
| Variant type | single nucleotide variant |
| Location | chr19:15243033-15243033 (GRCh38) |
| ClinVar | [VCV3716341](https://www.ncbi.nlm.nih.gov/clinvar/variation/3716341/) |

**All HGVS expressions:** `NC_000019.10:g.15243033C>T`, `NC_000019.9:g.15353844C>T`, `NM_001379291.1:c.3036G>A`, `NM_058243.3:c.3036G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -20, GERP -1.71 — fast-evolving / accelerated position
- CADD: **PHRED 0.061**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.29 acceptor 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 **0.0456%** (sas) · FAF95 0.0263% · FAF99 0.0206% · 12/26,302 in the highest group · 49/301,876 alleles overall — ultra-rare (popmax 0.0456%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0456% | 2,192 |
| European (non-Finnish) | 0.0161% | 6,198 |
| African / African-American | 0.00878% | 11,384 |
| Remaining individuals (not grpmax-eligible) | 0.00816% | 12,252 |

*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 **1012** lies in 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.Pro1012= 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-01 |

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

## Similar variants {#similar}

Related BRD4 variant pages (same residue, condition, or type): [BRD4 p.Pro1012Leu](/variant/brd4-p-pro1012leu), [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).

### 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 2026-10-14); 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 3716341). 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.*