# NM_001145358.2(SIN3A):c.1519_1523del (p.Phe507fs)

https://sugi.bio/variant/sin3a-p-phe507fs

## Summary

**SIN3A p.Phe507fs (c.1519_1523del)** is classified **Pathogenic** in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2542638826 · 1 submitter · 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.

*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 | [SIN3A](https://sugi.bio/atlas/gene/SIN3A/) |
| Protein change (HGVS p.) | p.Phe507fs |
| Coding change (HGVS c.) | c.1519_1523del |
| MANE Select transcript | [NM_001145358](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145358) |
| dbSNP | [rs2542638826](https://www.ncbi.nlm.nih.gov/snp/rs2542638826/) |
| Variant type | Deletion |
| Location | chr15:75401855-75401859 (GRCh38) |
| ClinVar | [VCV2811769](https://www.ncbi.nlm.nih.gov/clinvar/variation/2811769/) |

**All HGVS expressions:** `NC_000015.10:g.75401859_75401863del`, `NC_000015.9:g.75694200_75694204del`, `NG_052855.1:g.58925_58929del`, `NM_001145357.2:c.1519_1523del`, `NM_001145358.2:c.1519_1523del`, `NM_015477.3:c.1519_1523del`

## 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 -0.017, GERP -3.65, phastCons 0.768 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 10 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, 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):

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

## Protein context {#protein}

Residue **507** lies in the 'interaction with sap30' region; the pah 3 domain.

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.Phe507fs falls in the interaction with sap30 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related SIN3A variant pages (same residue, condition, or type): [SIN3A p.Phe507Leu](/variant/sin3a-p-phe507leu), [SIN3A p.Phe507Ser](/variant/sin3a-p-phe507ser), [SIN3A p.Lys937fs](/variant/sin3a-p-lys937fs), [SIN3A p.Lys948fs](/variant/sin3a-p-lys948fs), [SIN3A c.757-25_757-9del](/variant/sin3a-c-757-minus-25-757-minus-9del), [SIN3A p.His458_Gly459delinsArg](/variant/sin3a-p-his458-gly459delinsarg), [SIN3A p.Ala455fs](/variant/sin3a-p-ala455fs), [SIN3A p.Arg1134fs](/variant/sin3a-p-arg1134fs).

### 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 2026-07-14); 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 2811769). 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.*