Autosomal recessive nonsyndromic hearing loss 16

Summary

Autosomal recessive nonsyndromic hearing loss 16 (MONDO:0011364) is a disease caused by STRC (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: STRC (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 91

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 16
Mondo ID	MONDO:0011364
MeSH	C566339
OMIM	603720
DOID	DOID:0110471
UMLS	C1863561
MedGen	350211
GARD	0022597
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 16 · autosomal recessive nonsyndromic deafness 16 · autosomal recessive nonsyndromic deafness caused by mutation in STRC · autosomal recessive nonsyndromic deafness type 16 · autosomal recessive nonsyndromic hearing loss 16 · deafness, autosomal recessive 16 · deafness, autosomal recessive type 16 · DFNB16 · STRC autosomal recessive nonsyndromic deafness

Data availability: 91 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 16

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 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 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

91 retrieved; paginated sample, class counts are floors:

31 pathogenic, 14 uncertain significance, 11 pathogenic/likely pathogenic, 9 likely pathogenic, 7 benign, 7 benign/likely benign, 7 conflicting classifications of pathogenicity, 4 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1175705	NC_000015.9:g.(43851199_43890333)_(43897676_43924279)del	CATSPER2	Pathogenic	criteria provided, single submitter
1175707	NC_000015.9:g.(43851199_43890391)_(?_44038820)del	CATSPER2	Pathogenic	criteria provided, single submitter
562140	NC_000015.9:g.(43886857_43888004)_(43984930_43992627)del	CATSPER2	Pathogenic	criteria provided, single submitter
625827	GRCh37/hg19 15q15.3(chr15:43891364-43939659)	CATSPER2	Pathogenic	criteria provided, single submitter
625830	GRCh37/hg19 15q15.3(chr15:43890409-43939642)	CKMT1B	Pathogenic	criteria provided, single submitter
1799545	NC_000015.10:g.(?43890333)(43897714_?)del	FRMD5	Pathogenic	criteria provided, single submitter
1799546	NC_000015.10:g.(?43890333)(43893072_?)del	FRMD5	Pathogenic	criteria provided, single submitter
1800456	NC_000015.10:g.(?43890333)(43940887_?)del	FRMD5	Pathogenic	criteria provided, single submitter
560061	Single allele	LOC130056948	Pathogenic	criteria provided, single submitter
1174526	NC_000015.9:g.(43851199_43890333)_(43940820_44038794)del	PDIA3	Pathogenic/Likely pathogenic	criteria provided, single submitter
1323655	NM_153700.2(STRC):c.3958G>T (p.Glu1320Ter)	STRC	Pathogenic	criteria provided, single submitter
1325151	NM_153700.2(STRC):c.4510del (p.Glu1504fs)	STRC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165298	NM_153700.2(STRC):c.5188C>T (p.Arg1730Ter)	STRC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165302	NM_153700.2(STRC):c.4796_4800del (p.Cys1599fs)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
165305	NM_153700.2(STRC):c.4701+1G>A	STRC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165308	NM_153700.2(STRC):c.4425G>C (p.Trp1475Cys)	STRC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165315	NM_153700.2(STRC):c.3670C>T (p.Arg1224Ter)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
1687399	NM_153700.2(STRC):c.583C>T (p.Gln195Ter)	STRC	Pathogenic	criteria provided, single submitter
179758	NM_153700.2(STRC):c.4402C>T (p.Arg1468Ter)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
212742	NM_153700.2(STRC):c.4351C>T (p.Arg1451Ter)	STRC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228402	NM_153700.2(STRC):c.3217C>T (p.Arg1073Ter)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
242391	NM_153700.2(STRC):c.4057C>T (p.Gln1353Ter)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
2445651	NM_153700.2(STRC):c.2545C>T (p.Arg849Ter)	STRC	Pathogenic	criteria provided, single submitter
2582667	NM_153700.2(STRC):c.3823G>T (p.Glu1275Ter)	STRC	Pathogenic	criteria provided, single submitter
2582668	NM_153700.2(STRC):c.4096G>T (p.Gly1366Ter)	STRC	Pathogenic	criteria provided, single submitter
2582669	NM_153700.2(STRC):c.4484_4485del (p.Phe1495fs)	STRC	Pathogenic	criteria provided, single submitter
3250402	NM_153700.2(STRC):c.5185C>T (p.Arg1729Ter)	STRC	Pathogenic	criteria provided, single submitter
3252030	NM_153700.2(STRC):c.4819C>T (p.Gln1607Ter)	STRC	Pathogenic	criteria provided, single submitter
3359458	NM_153700.2(STRC):c.3922C>T (p.Gln1308Ter)	STRC	Pathogenic	criteria provided, multiple submitters, no conflicts
4291790	NM_153700.2(STRC):c.4816dup (p.Leu1606fs)	STRC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
STRC	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STRC	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
STRC	Orphanet:94064	Deafness-infertility syndrome
CATSPER2	Orphanet:94064	Deafness-infertility syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STRC	HGNC:16035	ENSG00000242866	Q7RTU9	Stereocilin	gencc,clinvar
CATSPER2	HGNC:18810	ENSG00000166762	Q96P56	Cation channel sperm-associated protein 2	clinvar
CKMT1B	HGNC:1995	ENSG00000237289	P12532	Creatine kinase U-type, mitochondrial	clinvar
FRMD5	HGNC:28214	ENSG00000171877	Q7Z6J6	FERM domain-containing protein 5	clinvar
PDIA3	HGNC:4606	ENSG00000167004	P30101	Protein disulfide-isomerase A3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STRC	Stereocilin	Essential to the formation of horizontal top connectors between outer hair cell stereocilia.
CATSPER2	Cation channel sperm-associated protein 2	Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel, that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acro…
CKMT1B	Creatine kinase U-type, mitochondrial	Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate).
FRMD5	FERM domain-containing protein 5	May be involved in regulation of cell migration.
PDIA3	Protein disulfide-isomerase A3	Protein disulfide isomerase that catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds in client proteins and functions as a protein folding chaperone.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Ion channel	1	22.3×	0.088
Enzyme (other)	2	4.8×	0.088
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STRC	Other/Unknown	no		Stereocilin-rel, Stereocilin_LRR
CATSPER2	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, CatSper2
CKMT1B	Enzyme (other)	yes	2.7.3.2	ATP-guanido_PTrfase, Gln_synth/guanido_kin_cat_dom, ATP-guanido_PTrfase_N
FRMD5	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, PH-like_dom_sf
PDIA3	Enzyme (other)	yes	5.3.4.1	PDI_thioredoxin-like_dom, Prot_disulphide_isomerase, Thioredoxin_domain

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	3
right hemisphere of cerebellum	3
cerebellar hemisphere	2
cerebellar vermis	1
cardiac muscle of right atrium	1
corpus callosum	1
left ventricle myocardium	1
caput epididymis	1
corpus epididymis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STRC	167		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CATSPER2	220	tissue_specific	yes	cerebellar vermis, right hemisphere of cerebellum, cerebellar cortex
CKMT1B	134		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FRMD5	191	broad	marker	cardiac muscle of right atrium, left ventricle myocardium, corpus callosum
PDIA3	295	ubiquitous	marker	corpus epididymis, stromal cell of endometrium, caput epididymis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDIA3	4,756
CKMT1B	1,687
CATSPER2	1,197
STRC	1,152
FRMD5	702

Intra-cohort edges

A	B	Sources
CATSPER2	CKMT1B	string_interaction
CATSPER2	STRC	string_interaction
CKMT1B	STRC	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CKMT1B	P12532	9
PDIA3	P30101	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FRMD5	Q7Z6J6	75.79
CATSPER2	Q96P56	69.83
STRC	Q7RTU9	69.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sperm Motility And Taxes	1	317.2×	0.022	CATSPER2
Creatine metabolism	1	259.6×	0.022	CKMT1B
Calnexin/calreticulin cycle	1	178.4×	0.022	PDIA3
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.030	PDIA3
Sensory processing of sound	1	77.2×	0.031	STRC
Maturation of DENV proteins	1	52.9×	0.033	PDIA3
Sensory processing of sound by outer hair cells of the cochlea	1	51.0×	0.033	STRC
Sensory processing of sound by inner hair cells of the cochlea	1	40.8×	0.036	STRC
ER-Phagosome pathway	1	32.4×	0.041	PDIA3
Sensory Perception	1	23.8×	0.050	STRC
Metabolism of amino acids and derivatives	1	16.9×	0.063	CKMT1B
Metabolism	1	2.9×	0.302	CKMT1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphocreatine biosynthetic process	1	674.1×	0.017	CKMT1B
peptide antigen assembly with MHC class I protein complex	1	561.7×	0.017	PDIA3
protein folding in endoplasmic reticulum	1	280.9×	0.017	PDIA3
cellular response to interleukin-7	1	259.3×	0.017	PDIA3
negative regulation of cell motility	1	259.3×	0.017	FRMD5
detection of mechanical stimulus involved in sensory perception of sound	1	187.2×	0.019	STRC
auditory receptor cell stereocilium organization	1	168.5×	0.019	STRC
sperm capacitation	1	134.8×	0.020	CATSPER2
actomyosin structure organization	1	112.3×	0.022	FRMD5
positive regulation of extrinsic apoptotic signaling pathway	1	91.1×	0.024	PDIA3
platelet aggregation	1	67.4×	0.027	PDIA3
fertilization	1	62.4×	0.027	CATSPER2
extrinsic apoptotic signaling pathway	1	61.3×	0.027	PDIA3
positive regulation of cell adhesion	1	54.4×	0.029	FRMD5
calcium ion transport	1	36.2×	0.038	CATSPER2
response to endoplasmic reticulum stress	1	33.4×	0.038	PDIA3
cell-matrix adhesion	1	32.7×	0.038	STRC
regulation of cell migration	1	31.5×	0.038	FRMD5
flagellated sperm motility	1	23.4×	0.049	CATSPER2
intracellular protein localization	1	20.9×	0.050	STRC
protein folding	1	20.7×	0.050	PDIA3
adaptive immune response	1	16.9×	0.058	PDIA3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STRC	0	0
CATSPER2	0	0
CKMT1B	0	0
FRMD5	0	0
PDIA3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PDIA3	14	Binding:12, ADMET:2
CKMT1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CKMT1B	2.7.3.2	creatine kinase
PDIA3	5.3.4.1	protein disulfide-isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	2	CKMT1B, PDIA3
D	Druggable family + AlphaFold only, no drug	1	CATSPER2
E	Difficult family or no structure, no drug	2	STRC, FRMD5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STRC	0	—
CATSPER2	0	—
CKMT1B	1	—
FRMD5	0	—
PDIA3	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.