Hearing loss, autosomal dominant 34, with or without inflammation

Summary

Hearing loss, autosomal dominant 34, with or without inflammation (MONDO:0033261) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 168

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, autosomal dominant 34, with or without inflammation
Mondo ID	MONDO:0033261
OMIM	617772
DOID	DOID:0080270
UMLS	C4521680
MedGen	1626346
GARD	0025790
Is cancer (heuristic)	no

Also known as: autosomal dominant nonsyndromic deafness 34 · deafness, autosomal dominant 34, with or without inflammation · DFNA34

Data availability: 168 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › hearing loss, autosomal dominant 34, with or without inflammation

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

168 retrieved; paginated sample, class counts are floors:

111 uncertain significance, 27 conflicting classifications of pathogenicity, 13 benign/likely benign, 12 likely benign, 3 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188124	NM_001243133.2(NLRP3):c.2575T>C (p.Tyr859His)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4370	NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4379	NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97960	NM_001243133.2(NLRP3):c.2576A>G (p.Tyr859Cys)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97987	NM_001243133.2(NLRP3):c.931G>A (p.Glu311Lys)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
1058144	NM_001243133.2(NLRP3):c.1371G>T (p.Glu457Asp)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446237	NM_001243133.2(NLRP3):c.2273T>C (p.Val758Ala)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1548717	NM_001243133.2(NLRP3):c.1650G>A (p.Lys550=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1980828	NM_001243133.2(NLRP3):c.800A>G (p.Gln267Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234288	NM_001243133.2(NLRP3):c.404G>A (p.Arg135His)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234304	NM_001243133.2(NLRP3):c.2611G>A (p.Ala871Thr)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234305	NM_001243133.2(NLRP3):c.2738C>T (p.Thr913Met)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2502900	NM_001243133.2(NLRP3):c.2630C>G (p.Ala877Gly)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296940	NM_001243133.2(NLRP3):c.203T>C (p.Met68Thr)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296947	NM_001243133.2(NLRP3):c.1361G>A (p.Gly454Glu)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3583443	NM_001243133.2(NLRP3):c.2769A>T (p.Gly923=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418133	NM_001243133.2(NLRP3):c.1625C>T (p.Thr542Met)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4371	NM_001243133.2(NLRP3):c.592G>A (p.Val198Met)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446409	NM_001243133.2(NLRP3):c.2753G>A (p.Arg918Gln)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449120	NM_001243133.2(NLRP3):c.638A>G (p.His213Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
536887	NM_001243133.2(NLRP3):c.1639A>T (p.Ser547Cys)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
583341	NM_001243133.2(NLRP3):c.2120C>A (p.Pro707Gln)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625986	NM_001243133.2(NLRP3):c.2098G>A (p.Asp700Asn)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
711518	NM_001243133.2(NLRP3):c.3048A>C (p.Leu1016Phe)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
787085	NM_001243133.2(NLRP3):c.2571A>G (p.Arg857=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875720	NM_001243133.2(NLRP3):c.122G>A (p.Arg41Lys)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
946043	NM_001243133.2(NLRP3):c.2686T>C (p.Ser896Pro)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
946684	NM_001243133.2(NLRP3):c.2982G>C (p.Gln994His)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952546	NM_001243133.2(NLRP3):c.564C>A (p.Ile188=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
953918	NM_001243133.2(NLRP3):c.1090C>A (p.Arg364=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP3	3,797

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP3	Q96P20	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
The NLRP3 inflammasome	1	671.8×	0.005	NLRP3
Purinergic signaling in leishmaniasis infection	1	423.0×	0.005	NLRP3
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.005	NLRP3
Metalloprotease DUBs	1	300.5×	0.005	NLRP3
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.005	NLRP3
Cytoprotection by HMOX1	1	184.2×	0.006	NLRP3
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.011	NLRP3

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
detection of biotic stimulus	1	4213.0×	0.003	NLRP3
negative regulation of acute inflammatory response	1	2407.4×	0.003	NLRP3
positive regulation of type 2 immune response	1	2407.4×	0.003	NLRP3
NLRP3 inflammasome complex assembly	1	2407.4×	0.003	NLRP3
positive regulation of T-helper 2 cell differentiation	1	2106.5×	0.003	NLRP3
osmosensory signaling pathway	1	1532.0×	0.003	NLRP3
positive regulation of T-helper 2 cell cytokine production	1	1532.0×	0.003	NLRP3
pattern recognition receptor signaling pathway	1	991.3×	0.004	NLRP3
positive regulation of interleukin-4 production	1	561.7×	0.005	NLRP3
negative regulation of interleukin-1 beta production	1	510.7×	0.005	NLRP3
pyroptotic inflammatory response	1	510.7×	0.005	NLRP3
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.005	NLRP3
positive regulation of interleukin-1 beta production	1	259.3×	0.008	NLRP3
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.008	NLRP3
defense response	1	216.1×	0.008	NLRP3
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.008	NLRP3
cellular response to virus	1	200.6×	0.008	NLRP3
regulation of inflammatory response	1	168.5×	0.009	NLRP3
protein maturation	1	163.6×	0.009	NLRP3
positive regulation of inflammatory response	1	145.3×	0.010	NLRP3
negative regulation of inflammatory response	1	137.0×	0.010	NLRP3
protein homooligomerization	1	122.1×	0.010	NLRP3
cellular response to lipopolysaccharide	1	98.0×	0.012	NLRP3
inflammatory response	1	37.7×	0.031	NLRP3
innate immune response	1	33.6×	0.033	NLRP3
apoptotic process	1	28.7×	0.038	NLRP3
signal transduction	1	16.1×	0.065	NLRP3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NLRP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NLRP3	CLOMIPHENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP3	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NLRP3	534

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

11 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)
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NLRP3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.