Otosclerosis 12

Summary

Otosclerosis 12 (MONDO:0968980) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 54

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	otosclerosis 12
Mondo ID	MONDO:0968980
OMIM	620792
UMLS	C5935610
MedGen	1856162
GARD	0027079
Is cancer (heuristic)	no

Data availability: 54 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › auditory system disorder › inner ear disorder › otosclerosis › otosclerosis 12

Related subtypes (10): otosclerosis 1, otosclerosis 2, otosclerosis 3, congenital corneal opacities, cornea guttata, and corectopia, otosclerosis 5, otosclerosis 4, otosclerosis 7, otosclerosis 8, otosclerosis 10, otosclerosis 11

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

54 retrieved; paginated sample, class counts are floors:

23 conflicting classifications of pathogenicity, 17 uncertain significance, 8 benign/likely benign, 2 benign, 2 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3892517	NC_000023.11:g.11088932_11088935del	HCCS-DT	Pathogenic	criteria provided, single submitter
1762032	NM_003072.5(SMARCA4):c.810dup (p.Gly271fs)	SMARCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
212237	NM_003072.5(SMARCA4):c.1791T>G (p.Pro597=)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238359	NM_003072.5(SMARCA4):c.1076G>A (p.Arg359Gln)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238428	NM_003072.5(SMARCA4):c.3436G>A (p.Gly1146Ser)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238450	NM_003072.5(SMARCA4):c.416C>T (p.Pro139Leu)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238475	NM_003072.5(SMARCA4):c.4417A>G (p.Lys1473Glu)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238491	NM_003072.5(SMARCA4):c.4817A>G (p.Gln1606Arg)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238503	NM_003072.5(SMARCA4):c.4916G>A (p.Arg1639His)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238507	NM_003072.5(SMARCA4):c.648G>C (p.Gln216His)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238516	NM_003072.5(SMARCA4):c.719C>T (p.Pro240Leu)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328037	NM_001387283.1(SMARCA4):c.4256G>A (p.Arg1419His)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391153	NM_003072.5(SMARCA4):c.4664C>T (p.Ser1555Leu)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408648	NM_003072.5(SMARCA4):c.4273A>T (p.Thr1425Ser)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408712	NM_003072.5(SMARCA4):c.1742A>G (p.Lys581Arg)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
470352	NM_003072.5(SMARCA4):c.3436G>T (p.Gly1146Cys)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
470465	NM_003072.5(SMARCA4):c.865A>G (p.Met289Val)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
484845	NM_003072.5(SMARCA4):c.355+4C>T	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
484864	NM_003072.5(SMARCA4):c.1030C>A (p.Pro344Thr)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
484868	NM_003072.5(SMARCA4):c.1706G>A (p.Arg569Gln)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486488	NM_003072.5(SMARCA4):c.4844G>A (p.Arg1615Gln)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486492	NM_003072.5(SMARCA4):c.4322A>G (p.Lys1441Arg)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
537788	NM_003072.5(SMARCA4):c.630G>T (p.Met210Ile)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
537827	NM_003072.5(SMARCA4):c.3216-3C>T	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
573389	NM_003072.5(SMARCA4):c.1725G>C (p.Gln575His)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011279	NM_003072.5(SMARCA4):c.4890C>G (p.Asp1630Glu)	SMARCA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1055913	NM_003072.5(SMARCA4):c.2859+3G>T	SMARCA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1313230	NM_003072.5(SMARCA4):c.239A>G (p.His80Arg)	SMARCA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
238401	NM_003072.5(SMARCA4):c.232T>C (p.Ser78Pro)	SMARCA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2918203	NM_003072.5(SMARCA4):c.881C>T (p.Ala294Val)	SMARCA4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
HCCS-DT	HGNC:55698	ENSG00000234129		HCCS divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
HCCS-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
cortical plate	1
ganglionic eminence	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
HCCS-DT	128		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
HCCS-DT	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCA4	P51532	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.012	SMARCA4
Formation of the canonical BAF (cBAF) complex	1	634.4×	0.012	SMARCA4
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.012	SMARCA4
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.012	SMARCA4
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.012	SMARCA4
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.012	SMARCA4
Regulation of endogenous retroelements	1	368.4×	0.012	SMARCA4
Interleukin-7 signaling	1	317.2×	0.012	SMARCA4
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.012	SMARCA4
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.012	SMARCA4
MITF-M-dependent gene expression	1	181.3×	0.014	SMARCA4
RMTs methylate histone arginines	1	146.4×	0.014	SMARCA4
Transcriptional regulation by RUNX1	1	146.4×	0.014	SMARCA4
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.014	SMARCA4
Formation of the beta-catenin:TCF transactivating complex	1	120.2×	0.014	SMARCA4
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.014	SMARCA4
TCF dependent signaling in response to WNT	1	117.7×	0.014	SMARCA4
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.014	SMARCA4
MITF-M-regulated melanocyte development	1	114.2×	0.014	SMARCA4
Signaling by WNT	1	112.0×	0.014	SMARCA4
Chromatin organization	1	81.6×	0.019	SMARCA4
Chromatin modifying enzymes	1	72.3×	0.019	SMARCA4
Epigenetic regulation of gene expression	1	71.4×	0.019	SMARCA4
Signaling by Interleukins	1	64.2×	0.021	SMARCA4
Nervous system development	1	42.9×	0.030	SMARCA4
Cytokine Signaling in Immune system	1	40.8×	0.030	SMARCA4
RNA Polymerase II Transcription	1	22.5×	0.053	SMARCA4
Gene expression (Transcription)	1	17.8×	0.064	SMARCA4
Generic Transcription Pathway	1	15.1×	0.073	SMARCA4
Developmental Biology	1	14.5×	0.074	SMARCA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of glucose mediated signaling pathway	1	5617.3×	0.005	SMARCA4
RNA polymerase I preinitiation complex assembly	1	3370.4×	0.005	SMARCA4
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	1532.0×	0.005	SMARCA4
positive regulation of signal transduction by p53 class mediator	1	1203.7×	0.005	SMARCA4
neural retina development	1	936.2×	0.005	SMARCA4
negative regulation of androgen receptor signaling pathway	1	936.2×	0.005	SMARCA4
host-mediated activation of viral transcription	1	887.0×	0.005	SMARCA4
nucleosome disassembly	1	802.5×	0.005	SMARCA4
regulation of G0 to G1 transition	1	674.1×	0.005	SMARCA4
regulation of nucleotide-excision repair	1	601.9×	0.005	SMARCA4
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.005	SMARCA4
positive regulation of T cell differentiation	1	455.5×	0.005	SMARCA4
positive regulation of Wnt signaling pathway	1	383.0×	0.005	SMARCA4
transcription initiation-coupled chromatin remodeling	1	383.0×	0.005	SMARCA4
positive regulation of myoblast differentiation	1	366.4×	0.005	SMARCA4
positive regulation of stem cell population maintenance	1	343.9×	0.005	SMARCA4
positive regulation of double-strand break repair	1	343.9×	0.005	SMARCA4
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.006	SMARCA4
positive regulation of miRNA transcription	1	290.6×	0.006	SMARCA4
negative regulation of cell differentiation	1	285.6×	0.006	SMARCA4
positive regulation of cell differentiation	1	267.5×	0.006	SMARCA4
heterochromatin formation	1	255.3×	0.006	SMARCA4
positive regulation of cold-induced thermogenesis	1	163.6×	0.009	SMARCA4
negative regulation of cell growth	1	144.0×	0.009	SMARCA4
chromatin remodeling	1	73.0×	0.018	SMARCA4
nervous system development	1	45.9×	0.027	SMARCA4
positive regulation of cell population proliferation	1	33.6×	0.035	SMARCA4
negative regulation of DNA-templated transcription	1	31.6×	0.036	SMARCA4
positive regulation of DNA-templated transcription	1	27.9×	0.039	SMARCA4
negative regulation of transcription by RNA polymerase II	1	17.7×	0.060	SMARCA4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCA4	2	2
HCCS-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMARCA4
CAMIBIRSTAT	2	SMARCA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCA4	230	Binding:207, ADMET:12, Functional:11

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SMARCA4	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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	SMARCA4
CAMIBIRSTAT	2	SMARCA4

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	SMARCA4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HCCS-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HCCS-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.