neuropathy, hereditary sensory and autonomic, type 1C

Summary

neuropathy, hereditary sensory and autonomic, type 1C (MONDO:0013337) is a disease caused by SPTLC2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SPTLC2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 579

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, hereditary sensory and autonomic, type 1C
Mondo ID	MONDO:0013337
OMIM	613640
DOID	DOID:0070157
UMLS	C3150896
MedGen	462246
GARD	0015683
Is cancer (heuristic)	no

Also known as: HSAN1C · neuropathy, hereditary sensory and autonomic, type IC

Data availability: 579 ClinVar variants · 5 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 1 › neuropathy, hereditary sensory and autonomic, type 1C

Related subtypes (5): neuropathy, hereditary sensory and autonomic, type 1A, neuropathy, hereditary sensory, type 1D, hereditary sensory neuropathy-deafness-dementia syndrome, neuropathy, hereditary sensory, type 1F, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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

579 retrieved; paginated sample, class counts are floors:

300 uncertain significance, 158 likely benign, 75 benign, 20 benign/likely benign, 19 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208302	NM_004863.4(SPTLC2):c.544G>C (p.Ala182Pro)	SPTLC2	Pathogenic	criteria provided, single submitter
2736856	NM_004863.4(SPTLC2):c.131A>G (p.Gln44Arg)	SPTLC2	Pathogenic	criteria provided, single submitter
4797	NM_004863.4(SPTLC2):c.1145G>T (p.Gly382Val)	SPTLC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
487224	NM_004863.4(SPTLC2):c.547C>T (p.Arg183Trp)	SPTLC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637418	NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)	SPTLC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685455	NM_004863.4(SPTLC2):c.545C>T (p.Ala182Val)	SPTLC2	Likely pathogenic	criteria provided, single submitter
857284	NM_004863.4(SPTLC2):c.1144G>C (p.Gly382Arg)	SPTLC2	Likely pathogenic	criteria provided, single submitter
1057415	NM_004863.4(SPTLC2):c.675G>T (p.Arg225Ser)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1349424	NM_004863.4(SPTLC2):c.1354C>T (p.Arg452Cys)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1423678	NM_004863.4(SPTLC2):c.180T>G (p.Asn60Lys)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1546258	NM_004863.4(SPTLC2):c.1304-5T>G	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1657143	NM_004863.4(SPTLC2):c.548G>A (p.Arg183Gln)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2740592	NM_004863.4(SPTLC2):c.1440C>T (p.Gly480=)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287675	NM_004863.4(SPTLC2):c.851-5T>C	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314578	NM_004863.4(SPTLC2):c.*5357A>G	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3711414	NM_004863.4(SPTLC2):c.496A>G (p.Ile166Val)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430350	NM_004863.4(SPTLC2):c.529A>G (p.Asn177Asp)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
478621	NM_004863.4(SPTLC2):c.1172A>G (p.Lys391Arg)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4798	NM_004863.4(SPTLC2):c.1075G>A (p.Val359Met)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538849	NM_004863.4(SPTLC2):c.119CCG[5] (p.Ala41_Ala42dup)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538854	NM_004863.4(SPTLC2):c.1470C>T (p.Asn490=)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
658265	NM_004863.4(SPTLC2):c.1070G>A (p.Arg357Gln)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
681064	NM_004863.4(SPTLC2):c.105AGCCGC[4] (p.Ala41_Ala42dup)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
839300	NM_004863.4(SPTLC2):c.1217T>C (p.Val406Ala)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885995	NM_004863.4(SPTLC2):c.*946C>A	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
939254	NM_004863.4(SPTLC2):c.778G>A (p.Glu260Lys)	SPTLC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446699	NC_000014.8:g.(?77743719)(78082922_?)del	ISM2	Uncertain significance	criteria provided, single submitter
1003505	NM_004863.4(SPTLC2):c.1060C>T (p.Pro354Ser)	SPTLC2	Uncertain significance	criteria provided, single submitter
1005402	NM_004863.4(SPTLC2):c.8C>T (p.Pro3Leu)	SPTLC2	Uncertain significance	criteria provided, single submitter
1009829	NM_004863.4(SPTLC2):c.467A>G (p.Tyr156Cys)	SPTLC2	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
SPTLC2	Definitive	Autosomal dominant	neuropathy, hereditary sensory and autonomic, type 1C	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTLC2	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
VIPAS39	Orphanet:2697	Arthrogryposis-renal dysfunction-cholestasis syndrome

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
SPTLC2	HGNC:11278	ENSG00000100596	O15270	Serine palmitoyltransferase 2	gencc,clinvar
VIPAS39	HGNC:20347	ENSG00000151445	Q9H9C1	Spermatogenesis-defective protein 39 homolog	clinvar
ISM2	HGNC:23176	ENSG00000100593	Q6H9L7	Isthmin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTLC2	Serine palmitoyltransferase 2	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
VIPAS39	Spermatogenesis-defective protein 39 homolog	Proposed to be involved in endosomal maturation implicating in part VPS33B.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
GPCR	1	8.0×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTLC2	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
VIPAS39	Other/Unknown	no		Vps16_C, Vps16_C_sf, Spe-39
ISM2	GPCR	yes		TSP1_rpt, AMOP_dom, TSP1_rpt_sf

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
corpus callosum	1
inferior vagus X ganglion	1
medial globus pallidus	1
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1
decidua	1
pancreatic ductal cell	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTLC2	274	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, medial globus pallidus
VIPAS39	274	ubiquitous	marker	cortical plate, ganglionic eminence, primordial germ cell in gonad
ISM2	115	tissue_specific	marker	decidua, placenta, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTLC2	2,335
VIPAS39	1,242
ISM2	1,196

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTLC2	O15270	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VIPAS39	Q9H9C1	78.66
ISM2	Q6H9L7	55.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Sphingolipid de novo biosynthesis	1	285.5×	0.012	SPTLC2
Sphingolipid metabolism	1	167.9×	0.012	SPTLC2
Metabolism of lipids	1	31.6×	0.042	SPTLC2
Metabolism	1	11.6×	0.086	SPTLC2

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
sphinganine biosynthetic process	1	4213.0×	0.003	SPTLC2
peptidyl-lysine hydroxylation	1	2106.5×	0.003	VIPAS39
positive regulation of lipophagy	1	1685.2×	0.003	SPTLC2
vacuolar transport	1	1404.3×	0.003	VIPAS39
sphingomyelin biosynthetic process	1	702.2×	0.004	SPTLC2
phagosome-lysosome fusion	1	648.1×	0.004	VIPAS39
collagen metabolic process	1	526.6×	0.004	VIPAS39
sphingosine biosynthetic process	1	526.6×	0.004	SPTLC2
post-translational protein modification	1	210.7×	0.008	VIPAS39
ceramide biosynthetic process	1	210.7×	0.008	SPTLC2
adipose tissue development	1	200.6×	0.008	SPTLC2
sphingolipid biosynthetic process	1	179.3×	0.008	SPTLC2
endosome to lysosome transport	1	168.5×	0.008	VIPAS39
collagen fibril organization	1	112.3×	0.011	VIPAS39
intracellular protein transport	1	32.4×	0.035	VIPAS39
spermatogenesis	1	17.6×	0.060	VIPAS39
cell differentiation	1	14.6×	0.068	VIPAS39

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
SPTLC2	0	0
VIPAS39	0	0
ISM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SPTLC2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPTLC2	2.3.1.50	serine C-palmitoyltransferase

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	1	SPTLC2
D	Druggable family + AlphaFold only, no drug	1	ISM2
E	Difficult family or no structure, no drug	1	VIPAS39

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)
SPTLC2	4	—
VIPAS39	0	—
ISM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.