SIN3A

Chr 15AD

SIN3 transcription regulator family member A

Also known as: CHR15DELq24, DEL15Q24, WITKOS

NCBI Gene: 25942 ENSG00000169375 UniProt: Q96ST3 OMIM: 607776

The protein is a transcriptional regulatory protein that mediates gene repression through protein-protein interactions via its paired amphipathic helix domains, including interactions with the Mad-Max transcriptional repressor complex. Loss-of-function mutations cause Witteveen-Kolk syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, which are important for protein-protein interactions and may mediate repression by the Mad-Max complex. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— SIN3A

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Gene-Disease Validity (ClinGen)

SIN3A-related intellectual disability syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

114 unique Pathogenic / Likely Pathogenic· 366 VUS of 803 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SIN3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 7.50

OE 0.01 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.39Z-score

OE missense 0.54 (0.49–0.59)

386 obs / 717.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.07)

0≤0.351.4

Missense OE?0.54 (0.49–0.59)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 67.4Missense obs/exp: 386 / 717.0Syn Z: 0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSIN3A-related syndromic intellectual disabilityLOFAD

This gene — mechanism propensity

0.2399th %ile

GOF

0.2597th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 89% of P/LP variants are LoF · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32938917 ↗

ClinVar Variant Classifications

803 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic70

Likely Pathogenic44

VUS366

Likely Benign253

Benign25

Conflicting26

Pathogenic

Likely Pathogenic

366

VUS

253

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	67	0	3	0	70
Likely Pathogenic	34	8	2	0	44
VUS	3	339	20	4	366
Likely Benign	0	12	72	169	253
Benign	0	2	14	9	25
Conflicting	—				26
Total	104	361	111	182	784

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

33 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap SIN3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →