SIN3A-related intellectual disability syndrome due to a point mutation

Summary

SIN3A-related intellectual disability syndrome due to a point mutation (MONDO:0044700) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 93
• Phenotypes (HPO): 20

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0410263	Brain imaging abnormality	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0032059	Mild malformation of cortical development	Frequent (30-79%)
HP:0040195	Decreased head circumference	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001808	Fragile nails	Occasional (5-29%)
HP:0002213	Fine hair	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0006989	Dysplastic corpus callosum	Occasional (5-29%)
HP:0030084	Clinodactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	SIN3A-related intellectual disability syndrome due to a point mutation
Mondo ID	MONDO:0044700
Orphanet	500166
UMLS	C4310804
MedGen	934771
GARD	0017925
Is cancer (heuristic)	no

Data availability: 93 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › SIN3A-related intellectual disability syndrome › SIN3A-related intellectual disability syndrome due to a point mutation

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

93 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 26 pathogenic, 20 likely pathogenic, 5 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 2 benign/likely benign, 1 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031165	NM_001145358.2(SIN3A):c.1229del (p.Lys410fs)	SIN3A	Pathogenic	criteria provided, single submitter
1031167	NM_001145358.2(SIN3A):c.2258_2259dup (p.Glu754fs)	SIN3A	Pathogenic	criteria provided, single submitter
1065454	NM_001145358.2(SIN3A):c.1015C>T (p.Gln339Ter)	SIN3A	Pathogenic	criteria provided, single submitter
1325072	NM_001145358.2(SIN3A):c.2803C>T (p.Arg935Ter)	SIN3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331651	NM_001145358.2(SIN3A):c.2152C>T (p.Arg718Ter)	SIN3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362953	NM_001145358.2(SIN3A):c.2353_2356del (p.Gln785fs)	SIN3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700222	NM_001145358.2(SIN3A):c.349C>T (p.Gln117Ter)	SIN3A	Pathogenic	criteria provided, single submitter
1709753	NM_001145358.2(SIN3A):c.172_173del (p.Val58fs)	SIN3A	Pathogenic	criteria provided, single submitter
1805544	NM_001145358.2(SIN3A):c.1411C>T (p.Arg471Ter)	SIN3A	Pathogenic	criteria provided, multiple submitters, no conflicts
2441706	NM_001145358.2(SIN3A):c.2506G>T (p.Glu836Ter)	SIN3A	Pathogenic	criteria provided, single submitter
2498622	NM_001145358.2(SIN3A):c.3025C>T (p.Gln1009Ter)	SIN3A	Pathogenic	criteria provided, single submitter
2504096	NM_001145358.2(SIN3A):c.3384dup	SIN3A	Pathogenic	criteria provided, single submitter
2527586	NM_001145358.2(SIN3A):c.3314dup (p.Tyr1105Ter)	SIN3A	Pathogenic	criteria provided, multiple submitters, no conflicts
253070	NM_001145358.2(SIN3A):c.803dup (p.Leu269fs)	SIN3A	Pathogenic	no assertion criteria provided
253071	NC_000015.10:g.75410285_75410288del	SIN3A	Pathogenic	criteria provided, single submitter
253072	NM_001145358.2(SIN3A):c.1759del (p.Ser587fs)	SIN3A	Pathogenic	no assertion criteria provided
253073	NM_001145358.2(SIN3A):c.2955_2956del (p.Glu985fs)	SIN3A	Pathogenic/Likely pathogenic	no assertion criteria provided
253074	NM_001145358.2(SIN3A):c.3310C>T (p.Arg1104Ter)	SIN3A	Pathogenic	no assertion criteria provided
3234067	NM_001145358.2(SIN3A):c.1810C>T (p.Gln604Ter)	SIN3A	Pathogenic	criteria provided, single submitter
3255060	NM_001145358.2(SIN3A):c.965dup (p.Asp323fs)	SIN3A	Pathogenic	criteria provided, single submitter
3255061	NM_001145358.2(SIN3A):c.1017_1021del (p.Arg340fs)	SIN3A	Pathogenic	criteria provided, single submitter
3370307	NM_001145358.2(SIN3A):c.2192_2198del (p.His731fs)	SIN3A	Pathogenic	criteria provided, single submitter
3774322	NM_001145358.2(SIN3A):c.2537_2538dup (p.Ala847fs)	SIN3A	Pathogenic	criteria provided, single submitter
3778748	NM_001145358.2(SIN3A):c.2669dup (p.Asn890fs)	SIN3A	Pathogenic	criteria provided, single submitter
3901523	NM_001145358.2(SIN3A):c.2764C>T (p.Arg922Ter)	SIN3A	Pathogenic	criteria provided, multiple submitters, no conflicts
4071009	NM_001145358.2(SIN3A):c.3418C>T (p.Arg1140Ter)	SIN3A	Pathogenic	criteria provided, single submitter
431101	NM_001145358.2(SIN3A):c.3118_3119del (p.Gln1040fs)	SIN3A	Pathogenic	criteria provided, single submitter
450723	NM_001145358.2(SIN3A):c.2809_2810del (p.Lys937fs)	SIN3A	Pathogenic	criteria provided, multiple submitters, no conflicts
450996	NM_001145358.2(SIN3A):c.2844_2847del (p.Lys948fs)	SIN3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4533313	NM_001145358.2(SIN3A):c.473+2T>A	SIN3A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SIN3A	Definitive	Autosomal dominant	SIN3A-related intellectual disability syndrome	8
SIN3B	Supportive	Autosomal dominant	SIN3A-related intellectual disability syndrome due to a point mutation	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIN3A	Orphanet:500166	SIN3-related intellectual disability syndrome due to a point mutation
SIN3A	Orphanet:94065	15q24 microdeletion syndrome
SIN3B	Orphanet:500166	SIN3-related intellectual disability syndrome due to a point mutation
ALX4	Orphanet:228390	Frontonasal dysplasia-alopecia-genital anomalies syndrome
ALX4	Orphanet:35093	Non-syndromic sagittal craniosynostosis
ALX4	Orphanet:52022	Potocki-Shaffer syndrome
ALX4	Orphanet:60015	Enlarged parietal foramina

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SIN3A	HGNC:19353	ENSG00000169375	Q96ST3	Paired amphipathic helix protein Sin3a	gencc,clinvar
SIN3B	HGNC:19354	ENSG00000127511	O75182	Paired amphipathic helix protein Sin3b	gencc
IMP3	HGNC:14497	ENSG00000177971	Q9NV31	U3 small nucleolar ribonucleoprotein protein IMP3	clinvar
ALX4	HGNC:450	ENSG00000052850	Q9H161	Homeobox protein aristaless-like 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SIN3A	Paired amphipathic helix protein Sin3a	Acts as a transcriptional repressor.
SIN3B	Paired amphipathic helix protein Sin3b	Acts as a transcriptional repressor.
IMP3	U3 small nucleolar ribonucleoprotein protein IMP3	Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP).
ALX4	Homeobox protein aristaless-like 4	Transcription factor involved in skull and limb development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SIN3A	Other/Unknown	no		PAH, HDAC_interact_dom, Sin3_C
SIN3B	Other/Unknown	no		PAH, HDAC_interact_dom, Sin3_C
IMP3	Other/Unknown	no		Ribosomal_uS4_N, S4_RNA-bd, Ribosomal_uS4
ALX4	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
ventricular zone	1
body of uterus	1
right ovary	1
right uterine tube	1
granulocyte	1
mucosa of transverse colon	1
skin of abdomen	1
buccal mucosa cell	1
cranial nerve II	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SIN3A	245	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
SIN3B	261	ubiquitous	marker	body of uterus, right uterine tube, right ovary
IMP3	287	ubiquitous	marker	mucosa of transverse colon, granulocyte, skin of abdomen
ALX4	82	broad	yes	primordial germ cell in gonad, buccal mucosa cell, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIN3A	4,666
IMP3	4,620
SIN3B	2,671
ALX4	1,162

Intra-cohort edges

A	B	Sources
SIN3A	SIN3B	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SIN3B	O75182	4
IMP3	Q9NV31	4
ALX4	Q9H161	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIN3A	Q96ST3	69.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative epigenetic regulation of rRNA expression	2	173.0×	0.002	SIN3A, SIN3B
Cytoprotection by HMOX1	2	122.8×	0.002	SIN3A, SIN3B
Transcriptional regulation by RUNX1	2	97.6×	0.002	SIN3A, SIN3B
Regulation of lipid metabolism by PPARalpha	2	94.0×	0.002	SIN3A, SIN3B
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	2	80.1×	0.002	SIN3A, SIN3B
NoRC negatively regulates rRNA expression	2	69.8×	0.002	SIN3A, SIN3B
Epigenetic regulation of gene expression	2	47.6×	0.004	SIN3A, SIN3B
Loss of MECP2 binding ability to 5mC-DNA	1	951.7×	0.006	SIN3A
Loss of function of MECP2 in Rett syndrome	1	475.8×	0.008	SIN3A
Pervasive developmental disorders	1	475.8×	0.008	SIN3A
MECP2 regulates transcription of neuronal ligands	1	475.8×	0.008	SIN3A
Disorders of Developmental Biology	1	475.8×	0.008	SIN3A
Disorders of Nervous System Development	1	475.8×	0.008	SIN3A
STAT3 nuclear events downstream of ALK signaling	1	346.1×	0.010	SIN3A
Regulation of MITF-M-dependent genes involved in apoptosis	1	211.5×	0.014	SIN3A
MECP2 regulates neuronal receptors and channels	1	200.3×	0.014	SIN3A
Signaling by ALK	1	190.3×	0.014	SIN3A
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	190.3×	0.014	SIN3A
RNA Polymerase II Transcription	2	15.0×	0.014	SIN3A, SIN3B
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.019	SIN3A
Regulation of MECP2 expression and activity	1	122.8×	0.019	SIN3A
FOXO-mediated transcription	1	112.0×	0.019	SIN3A
Transcriptional Regulation by MECP2	1	105.7×	0.019	SIN3A
Gene expression (Transcription)	2	11.9×	0.019	SIN3A, SIN3B
SUMOylation of transcription cofactors	1	81.0×	0.023	SIN3A
Generic Transcription Pathway	2	10.1×	0.023	SIN3A, SIN3B
rRNA modification in the nucleus and cytosol	1	62.4×	0.028	IMP3
MITF-M-dependent gene expression	1	60.4×	0.028	SIN3A
SUMO E3 ligases SUMOylate target proteins	1	59.5×	0.028	SIN3A
SUMOylation	1	54.4×	0.029	SIN3A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to methylglyoxal	1	4213.0×	0.005	SIN3A
cellular response to tert-butyl hydroperoxide	1	4213.0×	0.005	SIN3A
negative regulation of cell migration	2	55.8×	0.007	SIN3A, SIN3B
regulation of hormone levels	1	842.6×	0.013	SIN3A
cellular response to dopamine	1	601.9×	0.014	SIN3A
negative regulation of circadian rhythm	1	526.6×	0.014	SIN3A
regulation of axon extension	1	324.1×	0.018	SIN3A
cerebral cortex neuron differentiation	1	300.9×	0.018	SIN3A
negative regulation of protein localization to nucleus	1	210.7×	0.021	SIN3A
maturation of SSU-rRNA	1	191.5×	0.021	IMP3
negative regulation of stem cell population maintenance	1	191.5×	0.021	SIN3A
positive regulation of G2/M transition of mitotic cell cycle	1	150.5×	0.021	SIN3A
embryonic hindlimb morphogenesis	1	145.3×	0.021	ALX4
positive regulation of defense response to virus by host	1	131.7×	0.021	SIN3A
digestive tract development	1	131.7×	0.021	ALX4
embryonic forelimb morphogenesis	1	123.9×	0.021	ALX4
activation of innate immune response	1	120.4×	0.021	SIN3A
embryonic skeletal system morphogenesis	1	98.0×	0.024	ALX4
hair follicle development	1	95.8×	0.024	ALX4
type I interferon-mediated signaling pathway	1	86.0×	0.024	SIN3A
positive regulation of stem cell population maintenance	1	86.0×	0.024	SIN3A
embryonic digit morphogenesis	1	75.2×	0.026	ALX4
cellular response to glucose stimulus	1	66.9×	0.026	SIN3A
heterochromatin formation	1	63.8×	0.026	SIN3A
neuron development	1	63.8×	0.026	ALX4
rhythmic process	1	62.9×	0.026	SIN3A
roof of mouth development	1	62.0×	0.026	ALX4
hematopoietic progenitor cell differentiation	1	59.3×	0.026	SIN3A
ribosomal small subunit biogenesis	1	56.9×	0.026	IMP3
negative regulation of transcription by RNA polymerase II	2	8.9×	0.026	SIN3A, SIN3B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SIN3A	1	2
SIN3B	0	0
IMP3	0	0
ALX4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SIN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SIN3A	19	Binding:19

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	SIN3A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	SIN3A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SIN3B, IMP3, ALX4

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SIN3B	0	—
IMP3	0	—
ALX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.