Autosomal recessive nonsyndromic hearing loss 104

Summary

Autosomal recessive nonsyndromic hearing loss 104 (MONDO:0014675) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 104
Mondo ID	MONDO:0014675
OMIM	616515
DOID	DOID:0110465
UMLS	C4225298
MedGen	899775
GARD	0022654
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 104 · autosomal recessive nonsyndromic deafness 104 · autosomal recessive nonsyndromic deafness caused by mutation in RIPOR2 · autosomal recessive nonsyndromic deafness type 104 · deafness, autosomal recessive 104 · deafness, autosomal recessive type 104 · DFNB104 · RIPOR2 autosomal recessive nonsyndromic deafness

Data availability: 11 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 recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 104

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 44, 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 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

11 retrieved; paginated sample, class counts are floors:

4 benign, 2 uncertain significance, 2 pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208145	NM_001286445.3(RIPOR2):c.189-1G>A	RIPOR2	Pathogenic	no assertion criteria provided
2498247	NM_001286445.3(RIPOR2):c.1498C>T (p.Arg500Ter)	RIPOR2	Likely pathogenic	no assertion criteria provided
1680505	NM_001286445.3(RIPOR2):c.1164+482A>G	RIPOR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1680512	NM_001286445.3(RIPOR2):c.1142C>G (p.Thr381Ser)	RIPOR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1318100	NM_001286445.3(RIPOR2):c.502-10A>C	RIPOR2	Likely benign	criteria provided, multiple submitters, no conflicts
499652	NM_001286445.3(RIPOR2):c.2811T>C (p.Ser937=)	RIPOR2	Benign	criteria provided, multiple submitters, no conflicts
508154	NM_001286445.3(RIPOR2):c.2540G>A (p.Arg847Gln)	RIPOR2	Benign	criteria provided, multiple submitters, no conflicts
517548	NM_001286445.3(RIPOR2):c.*7G>A	RIPOR2	Benign	criteria provided, multiple submitters, no conflicts
517553	NM_001286445.3(RIPOR2):c.3043+9T>A	RIPOR2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
RIPOR2	Strong	Autosomal recessive	nonsyndromic genetic hearing loss	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIPOR2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RIPOR2	HGNC:13872	ENSG00000111913	Q9Y4F9	Rho family-interacting cell polarization regulator 2	gencc,clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIPOR2	Rho family-interacting cell polarization regulator 2	Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

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)
RIPOR2	Other/Unknown	no		ARM-like, ARM-type_fold, RIPOR3
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
blood	1
monocyte	1
mononuclear cell	1
gingiva	1
gingival epithelium	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIPOR2	250	broad	marker	blood, monocyte, mononuclear cell
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIPOR2	1,688
GJB2	1,391

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RIPOR2	Q9Y4F9	66.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oligomerization of connexins into connexons	1	1903.3×	0.002	GJB2
Transport of connexins along the secretory pathway	1	1903.3×	0.002	GJB2
Transport of connexons to the plasma membrane	1	271.9×	0.007	GJB2
Gap junction assembly	1	146.4×	0.010	GJB2
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.012	RIPOR2
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.012	RIPOR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of establishment of T cell polarity	1	8426.0×	1e-03	RIPOR2
negative regulation of protein localization to cell leading edge	1	8426.0×	1e-03	RIPOR2
sensory perception of sound	2	100.9×	1e-03	RIPOR2, GJB2
negative regulation of Rho guanyl-nucleotide exchange factor activity	1	4213.0×	0.001	RIPOR2
gap junction-mediated intercellular transport	1	1404.3×	0.003	GJB2
positive regulation of neutrophil extravasation	1	1203.7×	0.003	RIPOR2
negative regulation of T cell migration	1	1203.7×	0.003	RIPOR2
gap junction assembly	1	1053.2×	0.003	GJB2
positive regulation of myoblast fusion	1	526.6×	0.005	RIPOR2
cellular response to chemokine	1	495.6×	0.005	RIPOR2
regulation of establishment of cell polarity	1	468.1×	0.005	RIPOR2
negative regulation of Rho protein signal transduction	1	383.0×	0.005	RIPOR2
regulation of mitotic spindle assembly	1	366.4×	0.005	RIPOR2
positive regulation of neutrophil chemotaxis	1	324.1×	0.006	RIPOR2
positive regulation of filopodium assembly	1	280.9×	0.006	RIPOR2
negative regulation of cell adhesion	1	191.5×	0.008	RIPOR2
positive regulation of myoblast differentiation	1	183.2×	0.008	RIPOR2
negative regulation of T cell proliferation	1	165.2×	0.008	RIPOR2
transmembrane transport	1	84.3×	0.015	GJB2
muscle organ development	1	83.4×	0.015	RIPOR2
chemotaxis	1	68.0×	0.017	RIPOR2
regulation of cell cycle	1	37.3×	0.030	RIPOR2
cell-cell signaling	1	34.8×	0.031	GJB2
cell adhesion	1	18.7×	0.055	RIPOR2
cell differentiation	1	14.6×	0.068	RIPOR2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4
RIPOR2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
KANAMYCIN	4	GJB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
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	RIPOR2

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)
RIPOR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.