neuropathy, hereditary sensory and autonomic, type 2B

Summary

neuropathy, hereditary sensory and autonomic, type 2B (MONDO:0013142) is a disease caused by RETREG1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: RETREG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 82

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, hereditary sensory and autonomic, type 2B
Mondo ID	MONDO:0013142
OMIM	613115
DOID	DOID:0070150
UMLS	C2751092
MedGen	413474
GARD	0015618
Is cancer (heuristic)	no

Also known as: hereditary sensory and autonomic neuropathy type 2 caused by mutation in RETREG1 · HSAN2B · neuropathy, hereditary sensory and autonomic, type 2B · neuropathy, hereditary sensory and autonomic, type IIB · RETREG1 hereditary sensory and autonomic neuropathy type 2

Data availability: 82 ClinVar variants · 2 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 › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 2 › neuropathy, hereditary sensory and autonomic, type 2B

Related subtypes (2): neuropathy, hereditary sensory, type 2C, neuropathy, hereditary sensory and autonomic, type 2A

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

82 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 13 conflicting classifications of pathogenicity, 12 benign, 7 pathogenic, 4 benign/likely benign, 4 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
21257	NM_001034850.3(RETREG1):c.18_19del (p.Pro7fs)	LOC129993734	Pathogenic	criteria provided, multiple submitters, no conflicts
2497670	NM_001034850.3(RETREG1):c.102del (p.Ala35fs)	LOC129993734	Pathogenic	no assertion criteria provided
21259	NM_001034850.3(RETREG1):c.873+2T>C	RETREG1	Pathogenic	criteria provided, single submitter
328	NM_001034850.3(RETREG1):c.926C>G (p.Ser309Ter)	RETREG1	Pathogenic	criteria provided, multiple submitters, no conflicts
330	NM_001034850.3(RETREG1):c.433C>T (p.Gln145Ter)	RETREG1	Pathogenic	criteria provided, multiple submitters, no conflicts
915376	NM_001034850.3(RETREG1):c.458+2T>C	RETREG1	Pathogenic	criteria provided, single submitter
2581477	NM_001034850.3(RETREG1):c.34G>T (p.Glu12Ter)	RETREG1-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2428731	NM_001034850.3(RETREG1):c.775G>T (p.Glu259Ter)	RETREG1	Likely pathogenic	criteria provided, single submitter
538124	NM_001034850.3(RETREG1):c.22G>C (p.Glu8Gln)	LOC129993734	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538126	NM_001034850.3(RETREG1):c.86C>T (p.Pro29Leu)	LOC129993734	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907926	NM_001034850.3(RETREG1):c.10C>T (p.Pro4Ser)	LOC129993734	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203444	NM_001034850.3(RETREG1):c.826del (p.Ser276fs)	RETREG1	Conflicting classifications of pathogenicity	no assertion criteria provided
352686	NM_001034850.3(RETREG1):c.1089T>C (p.Asp363=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352687	NM_001034850.3(RETREG1):c.1013C>T (p.Pro338Leu)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352692	NM_001034850.3(RETREG1):c.723A>G (p.Lys241=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352695	NM_001034850.3(RETREG1):c.321-10G>A	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352698	NM_001034850.3(RETREG1):c.6G>C (p.Ala2=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
379338	NM_001034850.3(RETREG1):c.380G>A (p.Arg127His)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
703623	NM_001034850.3(RETREG1):c.1477C>T (p.Leu493=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904549	NM_001034850.3(RETREG1):c.900G>A (p.Glu300=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906951	NM_001034850.3(RETREG1):c.264C>T (p.Ser88=)	RETREG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451834	NM_001034850.3(RETREG1):c.137A>G (p.Glu46Gly)	LOC129993734	Uncertain significance	criteria provided, multiple submitters, no conflicts
538125	NM_001034850.3(RETREG1):c.17C>T (p.Pro6Leu)	LOC129993734	Uncertain significance	criteria provided, multiple submitters, no conflicts
904622	NM_001034850.2(RETREG1):c.-62C>A	LOC129993734	Uncertain significance	criteria provided, single submitter
906953	NM_001034850.3(RETREG1):c.94G>C (p.Ala32Pro)	LOC129993734	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413232	NM_001034850.3(RETREG1):c.321G>T (p.Trp107Cys)	RETREG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1943097	NM_001034850.3(RETREG1):c.631G>A (p.Gly211Arg)	RETREG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2063604	NM_001034850.3(RETREG1):c.321G>C (p.Trp107Cys)	RETREG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
352672	NM_001034850.3(RETREG1):c.*1641A>G	RETREG1	Uncertain significance	criteria provided, single submitter
352674	NM_001034850.3(RETREG1):c.*1160T>C	RETREG1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
RETREG1	Definitive	Autosomal recessive	neuropathy, hereditary sensory and autonomic, type 2B	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RETREG1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RETREG1	HGNC:25964	ENSG00000154153	Q9H6L5	Reticulophagy regulator 1	gencc,clinvar
RETREG1-AS1	HGNC:55551	ENSG00000246214		RETREG1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RETREG1	Reticulophagy regulator 1	Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes.

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)
RETREG1	Other/Unknown	no		RETREG1/3, RETR1_RHD, RETREG1-3-like_RHD
RETREG1-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RETREG1	283	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, diaphragm, heart right ventricle
RETREG1-AS1	149		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RETREG1	1,899
RETREG1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RETREG1	Q9H6L5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Dengue virus modulates apoptosis	1	713.8×	0.001	RETREG1

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
white fat cell differentiation	1	842.6×	0.004	RETREG1
reticulophagy	1	702.2×	0.004	RETREG1
endoplasmic reticulum organization	1	421.3×	0.004	RETREG1
collagen catabolic process	1	391.9×	0.004	RETREG1
sensory perception of pain	1	374.5×	0.004	RETREG1
mitophagy	1	318.0×	0.004	RETREG1
negative regulation of neuron apoptotic process	1	110.9×	0.009	RETREG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
RETREG1	0	0
RETREG1-AS1	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	2	RETREG1, RETREG1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RETREG1	0	—
RETREG1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.