# NM_001145358.2(SIN3A):c.1759del (p.Ser587fs)

https://sugi.bio/variant/sin3a-p-ser587fs

## Summary

**SIN3A p.Ser587fs (c.1759del)** is classified **Pathogenic** in SIN3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-08-12). No gnomAD frequency available for this variant; Associated with SIN3A-related intellectual disability syndrome due to a point mutation.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs879255620 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SIN3A gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to SIN3A-related intellectual disability syndrome due to a point mutation.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017925/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SIN3A](https://sugi.bio/atlas/gene/SIN3A/) |
| Protein change (HGVS p.) | p.Ser587fs |
| Coding change (HGVS c.) | c.1759del |
| MANE Select transcript | [NM_001145358](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145358) |
| dbSNP | [rs879255620](https://www.ncbi.nlm.nih.gov/snp/rs879255620/) |
| Variant type | Deletion |
| Location | chr15:75400135-75400135 (GRCh38) |
| ClinVar | [VCV253072](https://www.ncbi.nlm.nih.gov/clinvar/variation/253072/) |

**All HGVS expressions:** `NC_000015.10:g.75400137del`, `NC_000015.9:g.75692478del`, `NG_052855.1:g.60649del`, `NM_001145357.2:c.1759del`, `NM_001145358.2:c.1759del`, `NM_015477.3:c.1759del`

## 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 11.891, GERP 1.99, 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 0.14, 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 12 of 21**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**SIN3A** population constraint: LOEUF 0.14, pLI 1, missense-Z 5.1667; 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):

- **SIN3A-related intellectual disability syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **587** lies in the 'interaction with ncor1' region; the 'interaction with suds3 and sap130' region.

AlphaFold model confidence (whole protein): pLDDT 69.67, 26% of residues very-high.

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

*Describes the biological roles of SIN3A (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:** SIN3A's established molecular role includes transcription corepressor activity. p.Ser587fs falls in the interaction with ncor1 region. In Reactome, SIN3A is annotated in disease pathway(s) including **Loss of MECP2 binding ability to 5mC-DNA**.

**Disease mechanism (Reactome):** SIN3A loss or alteration is curated in [Loss of MECP2 binding ability to 5mC-DNA](https://reactome.org/content/detail/R-HSA-9022538).

### Pathways affected {#pathways}

SIN3A participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of MECP2 binding ability to 5mC-DNA](https://reactome.org/content/detail/R-HSA-9022538) | other |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | other |
| [FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes](https://reactome.org/content/detail/R-HSA-9615017) | other |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | other |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | other |
| [MECP2 regulates transcription of neuronal ligands](https://reactome.org/content/detail/R-HSA-9022702) | other |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | other |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | other |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | other |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | other |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | other |
| [Regulation of lipid metabolism by PPARalpha](https://reactome.org/content/detail/R-HSA-400206) | other |
| [STAT3 nuclear events downstream of ALK signaling](https://reactome.org/content/detail/R-HSA-9701898) | other |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | other |

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

**Molecular function:** transcription corepressor activity, RNA polymerase II-specific DNA-binding transcription factor binding, transcription regulator inhibitor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, activation of innate immune response, positive regulation of defense response to virus by host, heterochromatin formation, type I interferon-mediated signaling pathway, negative regulation of protein localization to nucleus.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-08-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-08-12 |

## Associated conditions {#conditions}

[SIN3A-related intellectual disability syndrome due to a point mutation](https://sugi.bio/atlas/disease/sin3a-related-intellectual-disability-syndrome-due-to-a-point-mutation/).

**Reported phenotype names (ClinVar):** SIN3A-related intellectual disability syndrome due to a point mutation, WITTEVEEN-KOLK SYNDROME, 15q24 Microdeletion Syndrome.

## Similar variants {#similar}

Related SIN3A variant pages (same residue, condition, or type): [SIN3A p.Lys937fs](/variant/sin3a-p-lys937fs), [SIN3A p.Lys948fs](/variant/sin3a-p-lys948fs), [SIN3A p.Arg340fs](/variant/sin3a-p-arg340fs), [SIN3A p.His731fs](/variant/sin3a-p-his731fs), [SIN3A p.Lys410fs](/variant/sin3a-p-lys410fs), [SIN3A p.Ser600fs](/variant/sin3a-p-ser600fs), [SIN3A p.Tyr1262fs](/variant/sin3a-p-tyr1262fs), [SIN3A p.Val58fs](/variant/sin3a-p-val58fs).

### 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 253072). 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.*