# NM_001145358.2(SIN3A):c.2127T>C (p.Ala709=)

https://sugi.bio/variant/sin3a-p-ala709

## Summary

**SIN3A p.Ala709= (c.2127T>C)** is classified **Likely benign** in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-16). Very rare (popmax 0.000169%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1359202744 · 1 submitter · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the SIN3A gene that is classified as likely benign — not considered disease-causing, 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.Ala709= |
| Coding change (HGVS c.) | c.2127T>C |
| MANE Select transcript | [NM_001145358](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145358) |
| dbSNP | [rs1359202744](https://www.ncbi.nlm.nih.gov/snp/rs1359202744/) |
| Variant type | single nucleotide variant |
| Location | chr15:75394830-75394830 (GRCh38) |
| ClinVar | [VCV794641](https://www.ncbi.nlm.nih.gov/clinvar/variation/794641/) |

**All HGVS expressions:** `NC_000015.10:g.75394830A>G`, `NC_000015.9:g.75687171A>G`, `NG_052855.1:g.65954T>C`, `NM_001145357.2:c.2127T>C`, `NM_001145358.2:c.2127T>C`, `NM_015477.3:c.2127T>C`

## 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 0.278, GERP -1.88, phastCons 0.008 — weakly conserved position
- CADD: **PHRED 8.104**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,974 in the highest group · 2/1,613,984 alleles overall — very rare (popmax 0.000169%, 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}

**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 **709** lies in the 'interaction with ncor1' region; the 'interaction with hdac1 and arid4b' 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.Ala709= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-11-16.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-11-16 |

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

## Similar variants {#similar}

Related SIN3A variant pages (same residue, condition, or type): [SIN3A p.Arg1140Ter](/variant/sin3a-p-arg1140ter), [SIN3A p.Arg471Ter](/variant/sin3a-p-arg471ter), [SIN3A p.Arg537Ter](/variant/sin3a-p-arg537ter), [SIN3A p.Arg553Ter](/variant/sin3a-p-arg553ter), [SIN3A p.Arg559Ter](/variant/sin3a-p-arg559ter), [SIN3A p.Arg718Ter](/variant/sin3a-p-arg718ter), [SIN3A p.Arg897Ter](/variant/sin3a-p-arg897ter), [SIN3A p.Arg935Ter](/variant/sin3a-p-arg935ter).

### 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 2026-10-14); 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 794641). 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.*