hearing loss, X-linked 4

Summary

hearing loss, X-linked 4 (MONDO:0010238) is a disease caused by SMPX (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SMPX (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, X-linked 4
Mondo ID	MONDO:0010238
MeSH	C564723
OMIM	300066
DOID	DOID:0111735
UMLS	C1848204
MedGen	376307
GARD	0018096
Is cancer (heuristic)	no

Also known as: deafness, nonsyndromic sensorineural progressive 6 · deafness, X-linked 4 · deafness, X-linked 4, X-linked dominant · deafness, X-linked type 4 · DFNX4 · SMPX X-linked nonsyndromic deafness · X-linked nonsyndromic deafness caused by mutation in SMPX

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › nonsyndromic genetic hearing loss › X-linked nonsyndromic hearing loss › hearing loss, X-linked 4

Related subtypes (5): hearing loss, X-linked 3, X-linked hereditary sensory and autonomic neuropathy with hearing loss, hearing loss, X-linked 6, X-linked mixed hearing loss with perilymphatic gusher, hearing loss, X-linked 1

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

21 retrieved; paginated sample, class counts are floors:

7 pathogenic, 7 uncertain significance, 4 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29945	NM_014332.3(SMPX):c.175G>T (p.Gly59Ter)	SMPX	Pathogenic	no assertion criteria provided
29946	NM_014332.3(SMPX):c.109G>T (p.Glu37Ter)	SMPX	Pathogenic	no assertion criteria provided
29947	NM_014332.3(SMPX):c.214G>T (p.Glu72Ter)	SMPX	Pathogenic	no assertion criteria provided
29948	NM_014332.3(SMPX):c.130del (p.Glu44fs)	SMPX	Pathogenic	no assertion criteria provided
3601795	NM_014332.3(SMPX):c.265T>C (p.Ter89Gln)	SMPX	Pathogenic	criteria provided, single submitter
3601797	NM_014332.3(SMPX):c.45+1G>T	SMPX	Pathogenic	criteria provided, single submitter
40063	NM_014332.3(SMPX):c.99del (p.Arg34fs)	SMPX	Pathogenic	no assertion criteria provided
445653	NM_014332.3(SMPX):c.99dup (p.Arg34fs)	SMPX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297079	NM_014332.3(SMPX):c.132+1G>A	SMPX	Likely pathogenic	no assertion criteria provided
3024082	NM_014332.3(SMPX):c.217del (p.Ile73fs)	SMPX	Likely pathogenic	no assertion criteria provided
417903	NM_014332.3(SMPX):c.133-1G>A	SMPX	Likely pathogenic	no assertion criteria provided
975949	NM_014332.3(SMPX):c.29del (p.Asn10fs)	SMPX	Likely pathogenic	criteria provided, single submitter
368151	NM_014332.3(SMPX):c.264G>A (p.Gln88=)	SMPX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368152	NM_014332.3(SMPX):c.132G>A (p.Glu44=)	SMPX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3234846	NM_014332.3(SMPX):c.197C>G (p.Pro66Arg)	SMPX	Uncertain significance	criteria provided, single submitter
368149	NM_014332.3(SMPX):c.*395T>G	SMPX	Uncertain significance	criteria provided, single submitter
368150	NM_014332.3(SMPX):c.*45A>T	SMPX	Uncertain significance	criteria provided, single submitter
368153	NM_014332.3(SMPX):c.-54G>A	SMPX	Uncertain significance	criteria provided, single submitter
913387	NM_014332.3(SMPX):c.*232T>G	SMPX	Uncertain significance	criteria provided, single submitter
913388	NM_014332.3(SMPX):c.*181A>G	SMPX	Uncertain significance	criteria provided, single submitter
914501	NM_014332.3(SMPX):c.-103C>T	SMPX	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
SMPX	Definitive	X-linked	nonsyndromic genetic hearing loss	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMPX	Orphanet:700163	SMPX-related distal myopathy
SMPX	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN

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
SMPX	HGNC:11122	ENSG00000091482	Q9UHP9	Small muscular protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPX	Small muscular protein	Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.

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)
SMPX	Other/Unknown	no		Chisel

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
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMPX	186	broad	marker	heart right ventricle, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMPX	1,066

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMPX	Q9UHP9	67.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
striated muscle contraction	1	842.6×	0.001	SMPX

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
SMPX	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	SMPX

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)
SMPX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.