# NM_152641.4(ARID2):c.820C>T (p.Arg274Ter)

https://sugi.bio/variant/arid2-p-arg274ter

## Summary

**ARID2 p.Arg274Ter (c.820C>T)** is classified **Pathogenic/Likely pathogenic** in ARID2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-10). No allele count reported in gnomAD v4.1 (AN 1,614,012); Associated with ARID2-related BAFopathy.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1943228378 · 2 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,614,012)

## For patients & families {#patients}

This is a change in the ARID2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to ARID2-related BAFopathy.

*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 | [ARID2](https://sugi.bio/atlas/gene/ARID2/) |
| Protein change (HGVS p.) | p.Arg274Ter |
| Coding change (HGVS c.) | c.820C>T |
| MANE Select transcript | [NM_152641](https://www.ncbi.nlm.nih.gov/nuccore/NM_152641) |
| dbSNP | [rs1943228378](https://www.ncbi.nlm.nih.gov/snp/rs1943228378/) |
| Variant type | single nucleotide variant |
| Location | chr12:45836788-45836788 (GRCh38) |
| ClinVar | [VCV1031208](https://www.ncbi.nlm.nih.gov/clinvar/variation/1031208/) |

**All HGVS expressions:** `NC_000012.11:g.46230571C>T`, `NC_000012.12:g.45836788C>T`, `NG_052800.1:g.112124C>T`, `NM_001347839.2:c.820C>T`, `NM_152641.4:c.820C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.20) — consistent with the pathogenic call
- Conservation: phyloP 7.665, GERP 2.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.224, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 21**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 46.0**. 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 deltas (raw): acceptor loss **0.17**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 35 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.21** (loss), gain 0.01 / loss 0.21. 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: **no allele count reported in gnomAD v4.1 (AN 1,614,012)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ARID2** population constraint: LOEUF 0.224, pLI 1, missense-Z 4.4902; 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)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 52.30, 16% of residues very-high.

**2 experimental structure(s)** (PDB): [7VDV](https://www.rcsb.org/structure/7VDV), [7Y8R](https://www.rcsb.org/structure/7Y8R).

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

*Describes the biological roles of ARID2 (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:** ARID2's established molecular role includes DNA binding.


### Pathways affected {#pathways}

ARID2 participates in **4 Reactome pathways** (⚕ = disease pathway):

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

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

**Molecular function:** DNA binding.

**Biological process:** nucleosome disassembly, negative regulation of cell population proliferation, negative regulation of cell migration, positive regulation of double-strand break repair via homologous recombination.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-10.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-02 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-06-10 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-10 |

## Associated conditions {#conditions}

[ARID2-related BAFopathy](https://sugi.bio/atlas/disease/arid2-related-bafopathy/), [Coffin-Siris syndrome 6](https://sugi.bio/atlas/disease/coffin-siris-syndrome-6/).

**Reported phenotype names (ClinVar):** ARID2-related BAFopathy, Coffin-Siris syndrome 6, not provided, none provided.

## Similar variants {#similar}

Related ARID2 variant pages (same residue, condition, or type): [ARID2 p.Arg1272Ter](/variant/arid2-p-arg1272ter), [ARID2 p.Arg1677Ter](/variant/arid2-p-arg1677ter), [ARID2 p.Arg1754Ter](/variant/arid2-p-arg1754ter), [ARID2 p.Gln920Ter](/variant/arid2-p-gln920ter), [ARID2 p.Asn302Ser](/variant/arid2-p-asn302ser), [ARID2 p.Glu112Ala](/variant/arid2-p-glu112ala), [ARID2 p.Glu1413Gly](/variant/arid2-p-glu1413gly), [ARID2 p.Ala1434Ser](/variant/arid2-p-ala1434ser).

### 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 1031208). 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.*