# NM_003072.5(SMARCA4):c.732G>A (p.Pro244=)

https://sugi.bio/variant/smarca4-p-pro244

## Summary

**SMARCA4 p.Pro244= (c.732G>A)** is classified **Benign/Likely benign** in SMARCA4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0233%, afr); Associated with rhabdoid tumor predisposition syndrome 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs878854241 · 7 submitters · 2 linked conditions · ultra-rare (popmax 0.0233%, afr)

## For patients & families {#patients}

This is a change in the SMARCA4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to rhabdoid tumor predisposition syndrome 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | SMARCA4 is a diagnostic-grade gene on 12 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018319/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.Pro244= |
| Coding change (HGVS c.) | c.732G>A |
| MANE Select transcript | [NM_003072](https://www.ncbi.nlm.nih.gov/nuccore/NM_003072) |
| dbSNP | [rs878854241](https://www.ncbi.nlm.nih.gov/snp/rs878854241/) |
| Variant type | single nucleotide variant |
| Location | chr19:10986565-10986565 (GRCh38) |
| ClinVar | [VCV238518](https://www.ncbi.nlm.nih.gov/clinvar/variation/238518/) |

**All HGVS expressions:** `LRG_878:g.30634G>A`, `LRG_878t1:c.732G>A`, `NC_000019.10:g.10986565G>A`, `NC_000019.9:g.11097241G>A`, `NG_011556.3:g.30634G>A`, `NM_001128844.3:c.732G>A`, `NM_001128845.2:c.732G>A`, `NM_001128846.2:c.732G>A`, `NM_001128847.4:c.732G>A`, `NM_001128848.2:c.732G>A`, `NM_001128849.3:c.732G>A`, `NM_001374457.1:c.732G>A`, `NM_001387283.1:c.732G>A`, `NM_003072.5:c.732G>A`, `NR_164683.1:n.908G>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 1.656, GERP -0.531, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.336**. 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: **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 **0.0233%** (afr) · FAF95 0.0147% · FAF99 0.0121% · 17/73,002 in the highest group · 49/1,537,374 alleles overall — ultra-rare (popmax 0.0233%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0233% | 4,294 |
| Remaining individuals (not grpmax-eligible) | 0.00667% | 14,995 |
| European (non-Finnish) | 0.00227% | 44,104 |
| Finnish (not grpmax-eligible) | 0.00216% | 46,262 |
| Admixed American | 0.00196% | 50,960 |

*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, triplosensitivity 0 (0–3 scale). *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 **244** lies in the 'necessary for interaction with ss18l1/crest' region; the 'disordered' region.

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.Pro244= falls in the necessary for interaction with ss18l1/crest 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-25.

**Submitter consensus:** conflicting (6 Likely benign, 1 benign).

**Submission history:** 7 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-04-05 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-08-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-11-30 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | benign | criteria provided, single submitter | clinical testing | 2025-07-05 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-01 |

## Associated conditions {#conditions}

[rhabdoid tumor predisposition syndrome 2](https://sugi.bio/atlas/disease/rhabdoid-tumor-predisposition-syndrome-2/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Rhabdoid tumor predisposition syndrome 2, Hereditary cancer-predisposing syndrome, SMARCA4-related disorder, not provided, not specified, SMARCA4-related condition, AllHighlyPenetrant, none provided, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related SMARCA4 variant pages (same residue, condition, or type): [SMARCA4 p.Pro244Arg](/variant/smarca4-p-pro244arg), [SMARCA4 p.Pro244Ser](/variant/smarca4-p-pro244ser), [SMARCA4 p.Pro244Leu](/variant/smarca4-p-pro244leu), [SMARCA4 p.Pro244_Ala245insGlyProGlyProGlyProGlyProGlyProGlyProGlyProGlyPro](/variant/smarca4-p-pro244-ala245insglyproglyproglyproglyproglyproglyprog-b039a443), [SMARCA4 p.Pro244_Ala245insGlyPro](/variant/smarca4-p-pro244-ala245insglypro), [SMARCA4 p.Pro244_Ala245insGlyProGlyPro](/variant/smarca4-p-pro244-ala245insglyproglypro), [SMARCA4 p.Pro244_Ala245insGlyProGlyProGlyProGlyPro](/variant/smarca4-p-pro244-ala245insglyproglyproglyproglypro), [SMARCA4 p.Pro244_Ala245insGlyProGlyProGlyProGlyProGlyPro](/variant/smarca4-p-pro244-ala245insglyproglyproglyproglyproglypro).

### 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 238518). 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.*