Autosomal dominant nonsyndromic hearing loss 1

Summary

Autosomal dominant nonsyndromic hearing loss 1 (MONDO:0007424) is a disease caused by DIAPH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: DIAPH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1,666

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 1
Mondo ID	MONDO:0007424
MeSH	C565121
OMIM	124900
DOID	DOID:0110541
UMLS	C1852282
MedGen	343767
GARD	0024557
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 1 · autosomal dominant nonsyndromic deafness 1 · autosomal dominant nonsyndromic deafness caused by mutation in DIAPH1 · autosomal dominant nonsyndromic deafness type 1 · deafness, autosomal dominant 1 · deafness, autosomal dominant 1, with or without thrombocytopenia · deafness, autosomal dominant type 1 · deafness, progressive Low tone · DFNA1 · DIAPH1 autosomal dominant nonsyndromic deafness · Konigsmark syndrome

Data availability: 1,666 ClinVar variants · 1 GenCC gene-disease record.

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 nonsyndromic hearing loss 1

Related subtypes (75): 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 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

600 retrieved; paginated sample, class counts are floors:

308 uncertain significance, 250 likely benign, 14 conflicting classifications of pathogenicity, 10 pathogenic, 6 benign/likely benign, 6 benign, 5 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070912	NM_005219.5(DIAPH1):c.108dup (p.Lys37Ter)	DIAPH1	Pathogenic	criteria provided, single submitter
1076722	NM_005219.5(DIAPH1):c.3022C>T (p.Arg1008Ter)	DIAPH1	Pathogenic	criteria provided, single submitter
1356050	NM_005219.5(DIAPH1):c.3166C>T (p.Gln1056Ter)	DIAPH1	Pathogenic	criteria provided, single submitter
1360681	NM_005219.5(DIAPH1):c.2100dup (p.Pro701fs)	DIAPH1	Pathogenic	criteria provided, single submitter
1395984	NM_005219.5(DIAPH1):c.2108dup (p.Pro704fs)	DIAPH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1402630	NM_005219.5(DIAPH1):c.1016del (p.Met339fs)	DIAPH1	Pathogenic	criteria provided, single submitter
1413320	NM_005219.5(DIAPH1):c.910dup (p.Ser304fs)	DIAPH1	Pathogenic	criteria provided, single submitter
183344	NM_005219.5(DIAPH1):c.2332C>T (p.Gln778Ter)	DIAPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1923492	NM_005219.5(DIAPH1):c.626dup (p.Tyr209Ter)	DIAPH1	Pathogenic	criteria provided, single submitter
1949957	NM_005219.5(DIAPH1):c.1483C>T (p.Arg495Ter)	DIAPH1	Pathogenic	criteria provided, single submitter
1990251	NM_005219.5(DIAPH1):c.1051C>T (p.Arg351Ter)	DIAPH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1030893	NM_005219.5(DIAPH1):c.145-1G>A	DIAPH1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1475715	NM_005219.5(DIAPH1):c.402+2T>C	DIAPH1	Likely pathogenic	criteria provided, single submitter
1485861	NM_005219.5(DIAPH1):c.1280+2T>G	DIAPH1	Likely pathogenic	criteria provided, single submitter
1487047	NM_005219.5(DIAPH1):c.621-2A>G	DIAPH1	Likely pathogenic	criteria provided, single submitter
2019843	NM_005219.5(DIAPH1):c.2676+2T>G	DIAPH1	Likely pathogenic	criteria provided, single submitter
1096112	NM_005219.5(DIAPH1):c.3552G>A (p.Glu1184=)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1129130	NM_005219.5(DIAPH1):c.3574+10G>A	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1194572	NM_005219.5(DIAPH1):c.117+8T>A	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336084	NM_005219.5(DIAPH1):c.300+7T>C	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1347677	NM_005219.5(DIAPH1):c.87G>A (p.Ala29=)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1348140	NM_005219.5(DIAPH1):c.1700C>T (p.Ala567Val)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1414598	NM_005219.5(DIAPH1):c.545C>A (p.Thr182Lys)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1435376	NM_005219.5(DIAPH1):c.2773G>A (p.Val925Met)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163074	NM_005219.5(DIAPH1):c.1364G>A (p.Arg455Gln)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1690797	NM_005219.5(DIAPH1):c.3111T>A (p.Phe1037Leu)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178340	NM_005219.5(DIAPH1):c.3050T>C (p.Met1017Thr)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178341	NM_005219.5(DIAPH1):c.2924A>G (p.Asn975Ser)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179391	NM_005219.5(DIAPH1):c.3099T>C (p.Asp1033=)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194639	NM_005219.5(DIAPH1):c.1736G>A (p.Arg579His)	DIAPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
DIAPH1	Definitive	Autosomal dominant	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DIAPH1	Orphanet:2573	Moyamoya disease
DIAPH1	Orphanet:477814	Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
DIAPH1	Orphanet:494444	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

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
DIAPH1	HGNC:2876	ENSG00000131504	O60610	Protein diaphanous homolog 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DIAPH1	Protein diaphanous homolog 1	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)
DIAPH1	Other/Unknown	no		Drf_DAD, FH3_dom, GTPase-bd

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
granulocyte	1
leukocyte	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DIAPH1	291	ubiquitous	marker	granulocyte, lower esophagus mucosa, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIAPH1	2,316

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DIAPH1	O60610	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Regulation of MITF-M dependent genes involved in invasion	1	2855.0×	0.003	DIAPH1
ERBB2 Regulates Cell Motility	1	713.8×	0.006	DIAPH1
RHOF GTPase cycle	1	259.6×	0.010	DIAPH1
RHOD GTPase cycle	1	203.9×	0.010	DIAPH1
RHOB GTPase cycle	1	154.3×	0.010	DIAPH1
RHOC GTPase cycle	1	146.4×	0.010	DIAPH1
RHO GTPases Activate Formins	1	77.7×	0.015	DIAPH1
RHOA GTPase cycle	1	74.6×	0.015	DIAPH1
Neutrophil degranulation	1	23.1×	0.043	DIAPH1

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
cellular response to histamine	1	2808.7×	0.003	DIAPH1
regulation of microtubule-based process	1	1872.4×	0.003	DIAPH1
protein localization to microtubule	1	1296.3×	0.003	DIAPH1
regulation of release of sequestered calcium ion into cytosol	1	936.2×	0.003	DIAPH1
regulation of cytoskeleton organization	1	648.1×	0.003	DIAPH1
actin filament polymerization	1	481.5×	0.003	DIAPH1
cytoskeleton organization	1	132.7×	0.010	DIAPH1
regulation of cell shape	1	123.0×	0.010	DIAPH1
sensory perception of sound	1	100.9×	0.011	DIAPH1
actin cytoskeleton organization	1	79.1×	0.013	DIAPH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DIAPH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DIAPH1	3	Binding:3

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	DIAPH1

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)
DIAPH1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.