Autosomal dominant auditory neuropathy 1

Summary

Autosomal dominant auditory neuropathy 1 (MONDO:0012196) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant auditory neuropathy 1
Mondo ID	MONDO:0012196
MeSH	C563790
OMIM	609129
DOID	DOID:0060690
UMLS	C1836743
MedGen	322984
GARD	0018127
Is cancer (heuristic)	no

Also known as: auditory neuropathy caused by mutation in DIAPH3 · auditory neuropathy, autosomal dominant, 1 · auditory neuropathy, autosomal dominant, type 1 · AUNA1 · autosomal dominant auditory neuropathy type 1 · DIAPH3 auditory neuropathy · NSDAN

Data availability: 24 ClinVar variants · 3 GenCC gene-disease records.

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 › autosomal dominant auditory neuropathy 1

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 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 34, with or without inflammation, 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

24 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 3 benign, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
984530	NM_001042517.2(DIAPH3):c.2059del (p.Cys687fs)	DIAPH3	Pathogenic	no assertion criteria provided
2955832	NM_001042517.2(DIAPH3):c.626+14T>C	DIAPH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449011	NM_001042517.2(DIAPH3):c.1840C>A (p.Pro614Thr)	DIAPH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1406036	NM_001042517.2(DIAPH3):c.1343G>A (p.Arg448Gln)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1415955	NM_001042517.2(DIAPH3):c.3055dup (p.Arg1019fs)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683845	NM_001042517.2(DIAPH3):c.2121A>C (p.Lys707Asn)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1686855	NC_000013.11:g.60163939G>A	DIAPH3	Uncertain significance	criteria provided, single submitter
1915046	NM_001042517.2(DIAPH3):c.3365A>G (p.Asn1122Ser)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
225339	NM_001042517.2(DIAPH3):c.2084_2088del (p.Glu695fs)	DIAPH3	Uncertain significance	criteria provided, single submitter
2440785	NM_001042517.2(DIAPH3):c.598C>T (p.Arg200Ter)	DIAPH3	Uncertain significance	criteria provided, single submitter
2440786	NM_001042517.2(DIAPH3):c.3142C>T (p.Arg1048Cys)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
31218	NC_000013.11:g.60163938C>T	DIAPH3	Uncertain significance	criteria provided, single submitter
3576339	NM_001042517.2(DIAPH3):c.2567A>G (p.Asn856Ser)	DIAPH3	Uncertain significance	criteria provided, single submitter
3600529	NM_001042517.2(DIAPH3):c.626G>T (p.Ser209Ile)	DIAPH3	Uncertain significance	criteria provided, single submitter
3901949	NM_001042517.2(DIAPH3):c.1385A>T (p.Asp462Val)	DIAPH3	Uncertain significance	criteria provided, single submitter
4073561	NM_001042517.2(DIAPH3):c.1361+2T>C	DIAPH3	Uncertain significance	criteria provided, single submitter
4685530	NM_001042517.2(DIAPH3):c.721A>G (p.Lys241Glu)	DIAPH3	Uncertain significance	criteria provided, single submitter
915388	NM_001042517.2(DIAPH3):c.1342C>T (p.Arg448Ter)	DIAPH3	Uncertain significance	criteria provided, single submitter
989303	NM_001042517.2(DIAPH3):c.357G>C (p.Glu119Asp)	DIAPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1255497	NM_001042517.2(DIAPH3):c.1014+27G>C	DIAPH3	Benign	criteria provided, multiple submitters, no conflicts
1255498	NM_001042517.2(DIAPH3):c.627-20G>A	DIAPH3	Benign	criteria provided, multiple submitters, no conflicts
508094	NM_001042517.2(DIAPH3):c.3028-4_3028-3insGTAA	DIAPH3	Benign	criteria provided, multiple submitters, no conflicts
514234	NM_001042517.2(DIAPH3):c.2149T>C (p.Ser717Pro)	DIAPH3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
522938	NM_001042517.2(DIAPH3):c.1439C>G (p.Thr480Arg)	DIAPH3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
DIAPH3	Limited	Autosomal dominant	autosomal dominant auditory neuropathy 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DIAPH3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

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
DIAPH3	HGNC:15480	ENSG00000139734	Q9NSV4	Protein diaphanous homolog 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DIAPH3	Protein diaphanous homolog 3	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.

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)
DIAPH3	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like

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
male germ cell	1
sperm	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DIAPH3	204	ubiquitous	marker	sperm, ventricular zone, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIAPH3	2,393

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DIAPH3	Q9NSV4	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
RHOF GTPase cycle	1	259.6×	0.012	DIAPH3
RHOD GTPase cycle	1	203.9×	0.012	DIAPH3
RHOJ GTPase cycle	1	200.3×	0.012	DIAPH3
RHOQ GTPase cycle	1	181.3×	0.012	DIAPH3
RHOB GTPase cycle	1	154.3×	0.012	DIAPH3
RHOG GTPase cycle	1	148.3×	0.012	DIAPH3
RHOC GTPase cycle	1	146.4×	0.012	DIAPH3
RAC2 GTPase cycle	1	126.9×	0.012	DIAPH3
RAC3 GTPase cycle	1	119.0×	0.012	DIAPH3
RHO GTPases Activate Formins	1	77.7×	0.015	DIAPH3
RHOA GTPase cycle	1	74.6×	0.015	DIAPH3
CDC42 GTPase cycle	1	72.3×	0.015	DIAPH3
RAC1 GTPase cycle	1	61.1×	0.016	DIAPH3

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
protein-containing complex remodeling	1	16852.0×	0.001	DIAPH3
erythrocyte enucleation	1	3370.4×	0.002	DIAPH3
inner ear receptor cell differentiation	1	3370.4×	0.002	DIAPH3
podosome assembly	1	2106.5×	0.002	DIAPH3
actin nucleation	1	1872.4×	0.002	DIAPH3
actin crosslink formation	1	1203.7×	0.002	DIAPH3
head development	1	1203.7×	0.002	DIAPH3
autophagosome-lysosome fusion	1	1203.7×	0.002	DIAPH3
microtubule polymerization	1	887.0×	0.003	DIAPH3
negative regulation of microtubule depolymerization	1	495.6×	0.004	DIAPH3
actin filament polymerization	1	481.5×	0.004	DIAPH3
macrophage differentiation	1	468.1×	0.004	DIAPH3
actin filament bundle assembly	1	455.5×	0.004	DIAPH3
establishment of cell polarity	1	383.0×	0.004	DIAPH3
cell projection organization	1	374.5×	0.004	DIAPH3
endosomal transport	1	244.2×	0.006	DIAPH3
chromosome segregation	1	173.7×	0.008	DIAPH3
integrin-mediated signaling pathway	1	160.5×	0.008	DIAPH3
cytoskeleton organization	1	132.7×	0.009	DIAPH3
sensory perception of sound	1	100.9×	0.011	DIAPH3
gene expression	1	79.9×	0.013	DIAPH3
actin cytoskeleton organization	1	79.1×	0.013	DIAPH3
in utero embryonic development	1	72.0×	0.014	DIAPH3

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DIAPH3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DIAPH3

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)
DIAPH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.