Autosomal recessive nonsyndromic hearing loss 44

Summary

Autosomal recessive nonsyndromic hearing loss 44 (MONDO:0012421) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 44
Mondo ID	MONDO:0012421
MeSH	C565716
OMIM	610154
DOID	DOID:0110501
UMLS	C1857809
MedGen	341854
GARD	0022620
Is cancer (heuristic)	no

Also known as: ADCY1 autosomal recessive nonsyndromic deafness · autosomal recessive deafness 44 · autosomal recessive nonsyndromic deafness 44 · autosomal recessive nonsyndromic deafness caused by mutation in ADCY1 · autosomal recessive nonsyndromic deafness type 44 · deafness, autosomal recessive 44 · deafness, autosomal recessive type 44 · DFNB44

Data availability: 9 ClinVar variants · 2 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 recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 44

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

9 retrieved; paginated sample, class counts are floors:

5 benign, 1 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 no classifications from unflagged records, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4845837	NM_021116.4(ADCY1):c.2410C>T (p.Gln804Ter)	ADCY1	Likely pathogenic	criteria provided, single submitter
1028721	NM_021116.4(ADCY1):c.2161A>G (p.Thr721Ala)	ADCY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139587	NM_021116.4(ADCY1):c.3112C>T (p.Arg1038Ter)	ADCY1	no classifications from unflagged records	no classifications from unflagged records
1188952	NM_021116.4(ADCY1):c.1149-31C>G	ADCY1	Benign	criteria provided, multiple submitters, no conflicts
1188953	NM_021116.4(ADCY1):c.1149-29T>C	ADCY1	Benign	criteria provided, multiple submitters, no conflicts
1188954	NM_021116.4(ADCY1):c.2571+37T>G	ADCY1	Benign	criteria provided, multiple submitters, no conflicts
1188955	NM_021116.4(ADCY1):c.2718+58G>A	ADCY1	Benign	criteria provided, multiple submitters, no conflicts
1272846	NM_021116.4(ADCY1):c.1789C>T (p.Arg597Trp)	ADCY1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
517532	NM_021116.4(ADCY1):c.3090G>A (p.Arg1030=)	ADCY1	Benign	criteria provided, multiple submitters, no conflicts

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
ADCY1	Supportive	Autosomal recessive	hearing loss, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADCY1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
ADCY1	HGNC:232	ENSG00000164742	Q08828	Adenylate cyclase type 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADCY1	Adenylate cyclase type 1	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADCY1	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADCY1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADCY1	1,731

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCY1	Q08828	78.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Adenylate cyclase activating pathway	1	1142.0×	0.008	ADCY1
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.008	ADCY1
Adenylate cyclase inhibitory pathway	1	761.3×	0.008	ADCY1
PKA activation in glucagon signalling	1	671.8×	0.008	ADCY1
PKA activation	1	634.4×	0.008	ADCY1
Activation of GABAB receptors	1	601.0×	0.008	ADCY1
PKA-mediated phosphorylation of CREB	1	571.0×	0.008	ADCY1
GABA B receptor activation	1	543.8×	0.008	ADCY1
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.008	ADCY1
Leishmania parasite growth and survival	1	393.8×	0.008	ADCY1
Calmodulin induced events	1	380.7×	0.008	ADCY1
CaM pathway	1	380.7×	0.008	ADCY1
Ca-dependent events	1	368.4×	0.008	ADCY1
Aquaporin-mediated transport	1	368.4×	0.008	ADCY1
Glucagon signaling in metabolic regulation	1	346.1×	0.008	ADCY1
G-protein mediated events	1	326.3×	0.008	ADCY1
DAG and IP3 signaling	1	317.2×	0.008	ADCY1
GABA receptor activation	1	317.2×	0.008	ADCY1
Response of endothelial cells to shear stress	1	300.5×	0.008	ADCY1
FCGR3A-mediated IL10 synthesis	1	292.8×	0.008	ADCY1
Opioid Signalling	1	265.6×	0.008	ADCY1
PLC beta mediated events	1	265.6×	0.008	ADCY1
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.008	ADCY1
Cellular responses to mechanical stimuli	1	259.6×	0.008	ADCY1
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.008	ADCY1
GPER1 signaling	1	248.3×	0.008	ADCY1
G alpha (z) signalling events	1	233.1×	0.008	ADCY1
Post NMDA receptor activation events	1	203.9×	0.009	ADCY1
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.009	ADCY1
Signaling by Hedgehog	1	184.2×	0.009	ADCY1

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
obsolete positive regulation of CREB transcription factor activity	1	1685.2×	0.003	ADCY1
neuroinflammatory response	1	1532.0×	0.003	ADCY1
cAMP biosynthetic process	1	1404.3×	0.003	ADCY1
cellular response to forskolin	1	1123.5×	0.003	ADCY1
cellular response to glucagon stimulus	1	842.6×	0.003	ADCY1
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.003	ADCY1
positive regulation of long-term synaptic potentiation	1	674.1×	0.003	ADCY1
renal water homeostasis	1	510.7×	0.004	ADCY1
presynaptic modulation of chemical synaptic transmission	1	455.5×	0.004	ADCY1
long-term memory	1	421.3×	0.004	ADCY1
regulation of circadian rhythm	1	259.3×	0.005	ADCY1
rhythmic process	1	251.5×	0.005	ADCY1
cellular response to calcium ion	1	200.6×	0.006	ADCY1
axonogenesis	1	160.5×	0.007	ADCY1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.009	ADCY1
intracellular signal transduction	1	38.1×	0.026	ADCY1

Therapeutics

Drug target analysis

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

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
ADCY1	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NB-001	3	ADCY1
COLFORSIN	2	ADCY1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADCY1	47	Binding:34, Functional:12, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY1	4.6.1.1	adenylate cyclase

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)
NB-001	3	ADCY1
COLFORSIN	2	ADCY1

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	ADCY1
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.