# NM_005104.4(BRD2):c.1876G>C (p.Ala626Pro)

https://sugi.bio/variant/brd2-p-ala626pro

## Summary

**BRD2 p.Ala626Pro (c.1876G>C)** is classified **Uncertain significance** in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0624); Very rare (popmax 0.000763%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the BRD2 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 | [BRD2](https://sugi.bio/atlas/gene/BRD2/) |
| Protein change (HGVS p.) | p.Ala626Pro |
| Coding change (HGVS c.) | c.1876G>C |
| MANE Select transcript | [NM_005104](https://www.ncbi.nlm.nih.gov/nuccore/NM_005104) |
| Variant type | single nucleotide variant |
| Location | chr6:32979862-32979862 (GRCh38) |
| ClinVar | [VCV4646584](https://www.ncbi.nlm.nih.gov/clinvar/variation/4646584/) |

**All HGVS expressions:** `NC_000006.11:g.32947639G>C`, `NC_000006.12:g.32979862G>C`, `NG_042801.1:g.16203G>C`, `NM_001113182.3:c.1876G>C`, `NM_001199455.1:c.1981G>C`, `NM_001199456.2:c.1735G>C`, `NM_001291986.2:c.1516G>C`, `NM_005104.4:c.1876G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0624)
- REVEL 0.044 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.26 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.495, GERP -2.7, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 16.65**. 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 1.05** across the covering region of the MANE Select transcript (32,976,605–32,979,879), spanning 3,274 bp. Chi-square p 0.26. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Pangolin: Δ**0.31** (gain), gain 0.31 / loss 0.16. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,179,916 in the highest group · 10/1,612,760 alleles overall — very rare (popmax 0.000763%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,456 |
| European (non-Finnish) (grpmax) | 0.000763% | 131,102 |

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}

**BRD2** population constraint: LOEUF 0.28, pLI 1, missense-Z -0.13697. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **626** lies in the 'disordered' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 65.70, 34% of residues very-high.

**169 experimental structure(s)** (PDB): [1X0J](https://www.rcsb.org/structure/1X0J), [2DVQ](https://www.rcsb.org/structure/2DVQ), [2DVR](https://www.rcsb.org/structure/2DVR), [2DVS](https://www.rcsb.org/structure/2DVS), [2DVV](https://www.rcsb.org/structure/2DVV), [2E3K](https://www.rcsb.org/structure/2E3K) — incl. mutant structure 4QEU.

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

*Describes the biological roles of BRD2 (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:** BRD2's established molecular role includes protein serine/threonine kinase activity. p.Ala626Pro falls in the disordered region.


### Pathways affected {#pathways}

BRD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RUNX3 regulates p14-ARF](https://reactome.org/content/detail/R-HSA-8951936) | curated |

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

**Molecular function:** protein serine/threonine kinase activity, histone H4K12ac reader activity, histone H4K5ac reader activity, histone H3K14ac reader activity, acetylation-dependent protein binding.

**Biological process:** nucleosome assembly, regulation of transcription by RNA polymerase II, protein localization to chromatin, chromatin looping, positive regulation of T-helper 17 cell lineage commitment.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BRD2 variant pages (same residue, condition, or type): [BRD2 p.Pro12Leu](/variant/brd2-p-pro12leu), [BRD2 p.Ala766Thr](/variant/brd2-p-ala766thr), [BRD2 p.Gln533=](/variant/brd2-p-gln533), [BRD2 p.Leu383=](/variant/brd2-p-leu383), [BRD2 p.Ser397=](/variant/brd2-p-ser397), [BRD2 p.Val465=](/variant/brd2-p-val465), [BRD2 p.Ala263Val](/variant/brd2-p-ala263val), [BRD2 p.Ala295Pro](/variant/brd2-p-ala295pro).

### 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 4646584). 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.*