neuropathy, hereditary motor and sensory, type 6B

Summary

neuropathy, hereditary motor and sensory, type 6B (MONDO:0014671) is a disease caused by SLC25A46 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SLC25A46 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 345

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, hereditary motor and sensory, type 6B
Mondo ID	MONDO:0014671
OMIM	616505
UMLS	C4225302
MedGen	895482
GARD	0018092
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease, type 6B · CMT6B · hereditary motor and sensory neuropathy type 6 caused by mutation in SLC25A46 · HMSN 6B · HMSN6B · neuropathy, hereditary motor and sensory, type 6B · neuropathy, hereditary motor and sensory, type VIB · SLC25A46 hereditary motor and sensory neuropathy type 6

Data availability: 345 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › motor peripheral neuropathy › neuropathy, hereditary motor and sensory, type 6B

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, Charcot-Marie-Tooth disease type 5, neuropathy, hereditary motor and sensory, type 6A, hereditary motor and sensory neuropathy, Okinawa type, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease axonal type 2C, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

345 retrieved; paginated sample, class counts are floors:

153 uncertain significance, 130 likely benign, 19 pathogenic, 14 benign, 11 conflicting classifications of pathogenicity, 10 likely pathogenic, 6 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
937658	NM_138773.2(SLC25A46):c.1_1257del	LOC129994345	Pathogenic	criteria provided, single submitter
1066712	NM_138773.4(SLC25A46):c.996C>G (p.Tyr332Ter)	SLC25A46	Pathogenic	criteria provided, single submitter
1071280	NC_000005.9:g.(?_110074821)_110097482del	SLC25A46	Pathogenic	criteria provided, single submitter
1441240	NM_138773.4(SLC25A46):c.618del (p.Lys206fs)	SLC25A46	Pathogenic	criteria provided, single submitter
2427269	NC_000005.9:g.(?110074821)(110097482_?)del	SLC25A46	Pathogenic	criteria provided, single submitter
2443748	NM_138773.4(SLC25A46):c.479G>C (p.Trp160Ser)	SLC25A46	Pathogenic	no assertion criteria provided
2742123	NM_138773.4(SLC25A46):c.304G>T (p.Gly102Ter)	SLC25A46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2762448	NM_138773.4(SLC25A46):c.462+2T>C	SLC25A46	Pathogenic	criteria provided, single submitter
2767905	NM_138773.4(SLC25A46):c.598_599dup (p.His202fs)	SLC25A46	Pathogenic	criteria provided, single submitter
372237	NM_138773.4(SLC25A46):c.166dup (p.His56fs)	SLC25A46	Pathogenic	criteria provided, single submitter
372239	NM_138773.4(SLC25A46):c.1005A>T (p.Glu335Asp)	SLC25A46	Pathogenic	no assertion criteria provided
372242	NM_138773.4(SLC25A46):c.1018C>T (p.Arg340Cys)	SLC25A46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374893	NM_138773.4(SLC25A46):c.413T>G (p.Leu138Arg)	SLC25A46	Pathogenic	no assertion criteria provided
422422	NM_138773.4(SLC25A46):c.11_12insTG (p.Arg5fs)	SLC25A46	Pathogenic	criteria provided, multiple submitters, no conflicts
4704727	NM_138773.4(SLC25A46):c.1006del (p.Thr336fs)	SLC25A46	Pathogenic	criteria provided, single submitter
652950	NC_000005.10:g.(?110743720)(110743797_?)del	SLC25A46	Pathogenic	criteria provided, single submitter
655776	NM_138773.4(SLC25A46):c.47del (p.Gly16fs)	SLC25A46	Pathogenic	criteria provided, single submitter
834307	NM_138773.4(SLC25A46):c.185_189del (p.Pro62fs)	SLC25A46	Pathogenic	criteria provided, single submitter
938735	NM_138773.4(SLC25A46):c.462+1G>A	SLC25A46	Pathogenic	criteria provided, single submitter
969384	NM_138773.4(SLC25A46):c.799_800dup (p.Thr268fs)	SLC25A46	Pathogenic	criteria provided, single submitter
374891	NM_001303250.3(SLC25A46):c.10+526_11-1368delinsGGCCGGGCGCG	TMEM232	Pathogenic	no assertion criteria provided
1334589	NM_138773.4(SLC25A46):c.479G>A (p.Trp160Ter)	SLC25A46	Likely pathogenic	criteria provided, single submitter
1468442	NM_138773.4(SLC25A46):c.385-2A>T	SLC25A46	Likely pathogenic	criteria provided, single submitter
3018331	NM_138773.4(SLC25A46):c.620+1G>A	SLC25A46	Likely pathogenic	criteria provided, single submitter
3022230	NM_138773.4(SLC25A46):c.327-2A>C	SLC25A46	Likely pathogenic	criteria provided, single submitter
3382951	NM_138773.4(SLC25A46):c.674T>G (p.Val225Gly)	SLC25A46	Likely pathogenic	criteria provided, single submitter
4738541	NM_138773.4(SLC25A46):c.620+1G>C	SLC25A46	Likely pathogenic	criteria provided, single submitter
488599	NM_138773.4(SLC25A46):c.736A>T (p.Arg246Ter)	SLC25A46	Likely pathogenic	criteria provided, single submitter
559386	NM_138773.4(SLC25A46):c.770G>A (p.Arg257Gln)	SLC25A46	Likely pathogenic	no assertion criteria provided
584411	NC_000005.9:g.(?110077728)(110083984_?)dup	SLC25A46	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
SLC25A46	Definitive	Autosomal recessive	neuropathy, hereditary motor and sensory, type 6B	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A46	Orphanet:2254	Pontocerebellar hypoplasia type 1
SLC25A46	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
INF2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
INF2	Orphanet:93114	Autosomal dominant intermediate Charcot-Marie-Tooth disease type E

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A46	HGNC:25198	ENSG00000164209	Q96AG3	Mitochondrial outer membrane protein SLC25A46	gencc,clinvar
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	clinvar
TMEM232	HGNC:37270	ENSG00000186952	C9JQI7	Transmembrane protein 232	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A46	Mitochondrial outer membrane protein SLC25A46	Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization.
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.
TMEM232	Transmembrane protein 232	Plays a critical role for male fertility and sperm motility by regulating sperm cytoplasm removal and maintaining axoneme integrity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A46	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, SLC25A46
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd
TMEM232	Other/Unknown	no		TMEM232

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
sperm	1
nerve	1
sural nerve	1
tibial nerve	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A46	290	ubiquitous	marker	sperm, secondary oocyte, oocyte
INF2	260	ubiquitous	marker	sural nerve, nerve, tibial nerve
TMEM232	173	broad	marker	bronchial epithelial cell, right uterine tube, bronchus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INF2	2,070
TMEM232	1,754
SLC25A46	1,557

Intra-cohort edges

A	B	Sources
SLC25A46	TMEM232	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INF2	Q27J81	10
SLC25A46	Q96AG3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM232	C9JQI7	73.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial membrane fission	1	2808.7×	0.003	SLC25A46
maintenance of protein complex location	1	2808.7×	0.003	TMEM232
spermatid cytoplasm removal during spermiation of flagellated sperm	1	2808.7×	0.003	TMEM232
peripheral nervous system neuron axonogenesis	1	1404.3×	0.004	SLC25A46
respiratory chain complex IV assembly	1	802.5×	0.005	SLC25A46
locomotion involved in locomotory behavior	1	802.5×	0.005	SLC25A46
regulation of mitochondrial fission	1	702.2×	0.005	INF2
mitochondrial transport	1	401.2×	0.005	SLC25A46
optic nerve development	1	401.2×	0.005	SLC25A46
mitochondrial fission	1	351.1×	0.005	SLC25A46
cerebellar Purkinje cell differentiation	1	351.1×	0.005	SLC25A46
cristae formation	1	351.1×	0.005	SLC25A46
phospholipid homeostasis	1	330.4×	0.005	SLC25A46
myelination in peripheral nervous system	1	295.6×	0.006	SLC25A46
autophagy of mitochondrion	1	244.2×	0.006	SLC25A46
actin filament polymerization	1	160.5×	0.009	INF2
axon development	1	151.8×	0.009	SLC25A46
dendrite development	1	130.6×	0.010	SLC25A46
cell projection organization	1	124.8×	0.010	TMEM232
synapse assembly	1	77.0×	0.015	SLC25A46
flagellated sperm motility	1	39.0×	0.027	TMEM232
protein-containing complex assembly	1	38.0×	0.027	SLC25A46
spermatogenesis	1	11.7×	0.083	TMEM232

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC25A46	0	0
INF2	0	0
TMEM232	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
INF2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	SLC25A46, INF2, TMEM232

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A46	0	—
INF2	1	—
TMEM232	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.