# NM_001172509.2(SATB2):c.1311_1314dup (p.Arg439fs)

https://sugi.bio/variant/satb2-p-arg439fs

## Summary

**SATB2 p.Arg439fs (c.1311_1314dup)** is classified **Pathogenic** in SATB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-08). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1559164234 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SATB2 gene that is reported as disease-causing, but on limited review, 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 | [SATB2](https://sugi.bio/atlas/gene/SATB2/) |
| Protein change (HGVS p.) | p.Arg439fs |
| Coding change (HGVS c.) | c.1311_1314dup |
| MANE Select transcript | [NM_001172509](https://www.ncbi.nlm.nih.gov/nuccore/NM_001172509) |
| dbSNP | [rs1559164234](https://www.ncbi.nlm.nih.gov/snp/rs1559164234/) |
| Variant type | Duplication |
| Location | chr2:199328769-199328770 (GRCh38) |
| ClinVar | [VCV587771](https://www.ncbi.nlm.nih.gov/clinvar/variation/587771/) |

**All HGVS expressions:** `NC_000002.11:g.200193496_200193499dup`, `NC_000002.12:g.199328773_199328776dup`, `NG_016976.2:g.147494_147497dup`, `NM_001172509.2:c.1311_1314dup`, `NM_001172517.1:c.1311_1314dup`, `NM_015265.3:c.1311_1314dupGGAG`, `NM_015265.4:c.1311_1314dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 4.782, GERP 2.47, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.077, 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 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**SATB2** population constraint: LOEUF 0.077, pLI 1, missense-Z 5.5263; 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):

- **SATB2 associated disorder** — Definitive (AD)

## Protein context {#protein}

Residue **439** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 66.87, 30% of residues very-high.

**3 experimental structure(s)** (PDB): [1WI3](https://www.rcsb.org/structure/1WI3), [1WIZ](https://www.rcsb.org/structure/1WIZ), [2CSF](https://www.rcsb.org/structure/2CSF).

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

*Describes the biological roles of SATB2 (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:** SATB2's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Arg439fs falls in the disordered region.


### Pathways affected {#pathways}

SATB2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-08.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-08 |

## 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 SATB2 variant pages (same residue, condition, or type): [SATB2 p.Arg439Trp](/variant/satb2-p-arg439trp), [SATB2 p.Gln270fs](/variant/satb2-p-gln270fs), [SATB2 p.Gln290Ter](/variant/satb2-p-gln290ter), [SATB2 p.Met418Arg](/variant/satb2-p-met418arg), [SATB2 p.Trp123Ter](/variant/satb2-p-trp123ter), [SATB2 p.Glu530Asp](/variant/satb2-p-glu530asp), [SATB2 p.Pro281Ala](/variant/satb2-p-pro281ala), [SATB2 p.Ser72Cys](/variant/satb2-p-ser72cys).

### 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 587771). 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.*