# NM_152641.4(ARID2):c.1615T>C (p.Ser539Pro)

https://sugi.bio/variant/arid2-p-ser539pro

## Summary

**ARID2 p.Ser539Pro (c.1615T>C)** is classified **Uncertain significance** in ARID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.9368); Very rare (popmax 0.00136%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00136%, nfe)

## For patients & families {#patients}

This is a change in the ARID2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Ser539Pro |
| Coding change (HGVS c.) | c.1615T>C |
| MANE Select transcript | [NM_152641](https://www.ncbi.nlm.nih.gov/nuccore/NM_152641) |
| Variant type | single nucleotide variant |
| Location | chr12:45848870-45848870 (GRCh38) |
| ClinVar | [VCV3784519](https://www.ncbi.nlm.nih.gov/clinvar/variation/3784519/) |

**All HGVS expressions:** `NC_000012.11:g.46242653T>C`, `NC_000012.12:g.45848870T>C`, `NG_052800.1:g.124206T>C`, `NM_001347839.2:c.1615T>C`, `NM_152641.4:c.1615T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9368)
- REVEL 0.583 (indeterminate)
- SaProt LLR -12.389 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.869, GERP 2.62, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.4**. 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 0.86** across the covering region of the MANE Select transcript (45,839,399–45,851,600), spanning 12,201 bp. Chi-square p 0.0001. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 16 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00136%** (nfe) · FAF95 0.000803% · FAF99 0.00065% · 16/1,178,910 in the highest group · 16/1,612,170 alleles overall — very rare (popmax 0.00136%, nfe).

*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}

Residue **539** lies in a DNA-binding region; a UniProt-annotated variant site (in css6).

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. p.Ser539Pro falls in a DNA-binding region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-07.

**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 | 2025-03-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ARID2 variant pages (same residue, condition, or type): [ARID2 p.Arg1769Ter](/variant/arid2-p-arg1769ter), [ARID2 p.Ala1335Glu](/variant/arid2-p-ala1335glu), [ARID2 p.Asn1280Asp](/variant/arid2-p-asn1280asp), [ARID2 p.Asp1400Gly](/variant/arid2-p-asp1400gly), [ARID2 p.Gln752Lys](/variant/arid2-p-gln752lys), [ARID2 p.Ile943Phe](/variant/arid2-p-ile943phe), [ARID2 p.Ser990Leu](/variant/arid2-p-ser990leu), [ARID2 p.Thr1474Ala](/variant/arid2-p-thr1474ala).

### 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 3784519). 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.*