# NM_001145358.2(SIN3A):c.624T>C (p.Val208=)

https://sugi.bio/variant/sin3a-p-val208

## Summary

**SIN3A p.Val208= (c.624T>C)** is classified **Likely benign** in SIN3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-11). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs758937437 · 2 submitters · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the SIN3A gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Val208= |
| Coding change (HGVS c.) | c.624T>C |
| MANE Select transcript | [NM_001145358](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145358) |
| dbSNP | [rs758937437](https://www.ncbi.nlm.nih.gov/snp/rs758937437/) |
| Variant type | single nucleotide variant |
| Location | chr15:75412895-75412895 (GRCh38) |
| ClinVar | [VCV2183306](https://www.ncbi.nlm.nih.gov/clinvar/variation/2183306/) |

**All HGVS expressions:** `NC_000015.10:g.75412895A>G`, `NC_000015.9:g.75705236A>G`, `NG_052855.1:g.47889T>C`, `NM_001145357.2:c.624T>C`, `NM_001145358.2:c.624T>C`, `NM_015477.3:c.624T>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 1.332, GERP -1.98, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 7.731**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.35 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00375% · FAF99 0.00337% · 1/6,078 in the highest group · 59/1,613,826 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,078 |
| European (non-Finnish) | 0.00475% | 21,071 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,238 |

*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 **208** lies in the 'interaction with rest' region; the 'disordered' 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.Val208= falls in the interaction with rest 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-17 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, 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 2183306). 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.*