# NM_003072.5(SMARCA4):c.2676G>A (p.Lys892=)

https://sugi.bio/variant/smarca4-p-lys892

## Summary

**SMARCA4 p.Lys892= (c.2676G>A)** is classified **Likely benign** in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-22). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SMARCA4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SMARCA4](https://sugi.bio/atlas/gene/SMARCA4/) |
| Protein change (HGVS p.) | p.Lys892= |
| Coding change (HGVS c.) | c.2676G>A |
| MANE Select transcript | [NM_003072](https://www.ncbi.nlm.nih.gov/nuccore/NM_003072) |
| Variant type | single nucleotide variant |
| Location | chr19:11021784-11021784 (GRCh38) |
| ClinVar | [VCV3958473](https://www.ncbi.nlm.nih.gov/clinvar/variation/3958473/) |

**All HGVS expressions:** `LRG_878:g.65853G>A`, `LRG_878t1:c.2676G>A`, `NC_000019.10:g.11021784G>A`, `NC_000019.9:g.11132460G>A`, `NG_011556.3:g.65853G>A`, `NM_001128844.3:c.2676G>A`, `NM_001128845.2:c.2676G>A`, `NM_001128846.2:c.2676G>A`, `NM_001128847.4:c.2676G>A`, `NM_001128848.2:c.2676G>A`, `NM_001128849.3:c.2676G>A`, `NM_001374457.1:c.2676G>A`, `NM_001387283.1:c.2676G>A`, `NM_001411150.1:c.2676G>A`, `NM_003072.5:c.2676G>A`, `NR_164683.1:n.2966G>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 2.856, GERP -1.33, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.5**. 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 (G>T, Δ0.41 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**SMARCA4** population constraint: LOEUF 0.226, pLI 1, missense-Z 8.811; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **Coffin-Siris syndrome** — Definitive (AD)
- **rhabdoid tumor predisposition syndrome 2** — Definitive (AD)
- **hereditary nonpolyposis colon cancer** — Limited (AD)

## Protein context {#protein}

Residue **892** lies in an α-helix; the 'sufficient for interaction with dlx1' region; the helicase atp-binding domain.

AlphaFold model confidence (whole protein): pLDDT 65.38, 20% of residues very-high.

**31 experimental structure(s)** (PDB): [2GRC](https://www.rcsb.org/structure/2GRC), [2H60](https://www.rcsb.org/structure/2H60), [3UVD](https://www.rcsb.org/structure/3UVD), [5DKD](https://www.rcsb.org/structure/5DKD), [5EA1](https://www.rcsb.org/structure/5EA1), [6BGH](https://www.rcsb.org/structure/6BGH).

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

*Describes the biological roles of SMARCA4 (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:** SMARCA4's established molecular role includes transcription coregulator binding. p.Lys892= falls in the sufficient for interaction with dlx1 region.


### Pathways affected {#pathways}

SMARCA4 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chromatin modifying enzymes](https://reactome.org/content/detail/R-HSA-3247509) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [Formation of the canonical BAF (cBAF) complex](https://reactome.org/content/detail/R-HSA-9933937) | curated |
| [Formation of the embryonic stem cell BAF (esBAF) complex](https://reactome.org/content/detail/R-HSA-9933946) | curated |
| [Formation of the non-canonical BAF (ncBAF) complex](https://reactome.org/content/detail/R-HSA-9933947) | curated |
| [Formation of the polybromo-BAF (pBAF) complex](https://reactome.org/content/detail/R-HSA-9933939) | curated |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [RMTs methylate histone arginines](https://reactome.org/content/detail/R-HSA-3214858) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [SWI/SNF chromatin remodelers](https://reactome.org/content/detail/R-HSA-9932451) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | electronic |
| [Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)](https://reactome.org/content/detail/R-HSA-9934037) | electronic |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | electronic |
| [Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)](https://reactome.org/content/detail/R-HSA-9845323) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** transcription coregulator binding, p53 binding, transcription coactivator activity, transcription corepressor activity, ATP-dependent activity, acting on DNA, Tat protein binding.

**Biological process:** neural retina development, nucleosome disassembly, chromatin remodeling, positive regulation of Wnt signaling pathway, negative regulation of cell growth, host-mediated activation of viral transcription.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-22 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related SMARCA4 variant pages (same residue, condition, or type): [SMARCA4 c.1943+1G>A](/variant/smarca4-c-1943-plus-1g-a), [SMARCA4 c.2438+1G>A](/variant/smarca4-c-2438-plus-1g-a), [SMARCA4 c.3216-1G>C](/variant/smarca4-c-3216-minus-1g-c), [SMARCA4 c.3546+1G>A](/variant/smarca4-c-3546-plus-1g-a), [SMARCA4 c.3774+2T>A](/variant/smarca4-c-3774-plus-2t-a), [SMARCA4 c.3951+2T>C](/variant/smarca4-c-3951-plus-2t-c), [SMARCA4 c.3952-1G>A](/variant/smarca4-c-3952-minus-1g-a), [SMARCA4 p.Arg1005Ter](/variant/smarca4-p-arg1005ter).

### 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 3958473). 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.*