# NM_001330288.2(SMARCC2):c.705G>A (p.Arg235=)

https://sugi.bio/variant/smarcc2-p-arg235

## Summary

**SMARCC2 p.Arg235= (c.705G>A)** is classified **Likely benign** in SMARCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-14). Very rare (popmax 0.0011%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the SMARCC2 gene that is classified as likely benign — not considered disease-causing, 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 | [SMARCC2](https://sugi.bio/atlas/gene/SMARCC2/) |
| Protein change (HGVS p.) | p.Arg235= |
| Coding change (HGVS c.) | c.705G>A |
| MANE Select transcript | [NM_001330288](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330288) |
| Variant type | single nucleotide variant |
| Location | chr12:56182007-56182007 (GRCh38) |
| ClinVar | [VCV4917216](https://www.ncbi.nlm.nih.gov/clinvar/variation/4917216/) |

**All HGVS expressions:** `NC_000012.11:g.56575791C>T`, `NC_000012.12:g.56182007C>T`, `NG_047081.1:g.12561G>A`, `NM_001130420.3:c.705G>A`, `NM_001330288.2:c.705G>A`, `NM_003075.5:c.705G>A`, `NM_139067.4:c.705G>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 -0.128, GERP -0.272, phastCons 0.422 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.33**. 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, Δ0.20 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 **0.0011%** (sas) · 1/90,624 in the highest group · 1/1,610,906 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**SMARCC2** population constraint: LOEUF 0.167, pLI 1, missense-Z 4.8274. *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)

## Protein context {#protein}

Residue **235** lies in the brct; c-terminus domain; the 'marr-like, brct and chromo domains module' region.

AlphaFold model confidence (whole protein): pLDDT 64.89, 30% of residues very-high.

**9 experimental structure(s)** (PDB): [6KAG](https://www.rcsb.org/structure/6KAG), [6LTH](https://www.rcsb.org/structure/6LTH), [6LTJ](https://www.rcsb.org/structure/6LTJ), [7VDV](https://www.rcsb.org/structure/7VDV), [7Y8R](https://www.rcsb.org/structure/7Y8R), [9RL4](https://www.rcsb.org/structure/9RL4).

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

*Describes the biological roles of SMARCC2 (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.*


### Pathways affected {#pathways}

SMARCC2 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [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 |
| [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}

**Biological process:** nucleosome disassembly, chromatin remodeling, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-14 |

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

## Similar variants {#similar}

Related SMARCC2 variant pages (same residue, condition, or type): [SMARCC2 c.1311-3C>G](/variant/smarcc2-c-1311-minus-3c-g), [SMARCC2 c.1926+1G>A](/variant/smarcc2-c-1926-plus-1g-a), [SMARCC2 c.1926+1G>T](/variant/smarcc2-c-1926-plus-1g-t), [SMARCC2 c.1926+2T>C](/variant/smarcc2-c-1926-plus-2t-c), [SMARCC2 p.Arg116His](/variant/smarcc2-p-arg116his), [SMARCC2 p.Arg192Ter](/variant/smarcc2-p-arg192ter), [SMARCC2 p.Arg269Ter](/variant/smarcc2-p-arg269ter), [SMARCC2 p.Arg474Ter](/variant/smarcc2-p-arg474ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4917216). 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.*