Spastic paraplegia 18a, autosomal dominant

Summary

Spastic paraplegia 18a, autosomal dominant (MONDO:0957788) is a disease caused by ERLIN2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ERLIN2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 18a, autosomal dominant
Mondo ID	MONDO:0957788
OMIM	620512
DOID	DOID:0070640
UMLS	C5882694
MedGen	1844217
GARD	0026873
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 18 › spastic paraplegia 18a, autosomal dominant

Related subtypes (1): spastic paraplegia 18b, autosomal recessive

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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2583112	NM_007175.8(ERLIN2):c.386G>C (p.Ser129Thr)	ERLIN2	Pathogenic	no assertion criteria provided
458243	NM_007175.8(ERLIN2):c.452C>T (p.Ala151Val)	ERLIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956477	NM_007175.8(ERLIN2):c.502G>A (p.Val168Met)	ERLIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293926	NM_007175.8(ERLIN2):c.424+957C>T	ERLIN2	Uncertain significance	criteria provided, single submitter
4532094	NM_007175.8(ERLIN2):c.200A>G (p.Gln67Arg)	ERLIN2	Uncertain significance	criteria provided, single submitter
4796689	NM_007175.8(ERLIN2):c.487C>G (p.Leu163Val)	ERLIN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ERLIN2	Strong	Autosomal recessive	hereditary spastic paraplegia 18	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERLIN2	Orphanet:209951	Autosomal spastic paraplegia type 18
ERLIN2	Orphanet:247604	Juvenile primary lateral sclerosis
ERLIN2	Orphanet:280384	Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome

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
ERLIN2	HGNC:1356	ENSG00000147475	O94905	Erlin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERLIN2	Erlin-2	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.

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)
ERLIN2	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf

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
calcaneal tendon	1
choroid plexus epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERLIN2	277	ubiquitous	marker	choroid plexus epithelium, renal medulla, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERLIN2	2,170

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERLIN2	O94905	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 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
Signaling by plasma membrane FGFR1 fusions	1	2855.0×	0.002	ERLIN2
Signaling by FGFR1 in disease	1	292.8×	0.006	ERLIN2
Defective CFTR causes cystic fibrosis	1	219.6×	0.006	ERLIN2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	193.6×	0.006	ERLIN2
ABC-family protein mediated transport	1	121.5×	0.008	ERLIN2

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
negative regulation of cholesterol biosynthetic process	1	2407.4×	0.001	ERLIN2
SREBP signaling pathway	1	1872.4×	0.001	ERLIN2
regulation of cholesterol biosynthetic process	1	1532.0×	0.001	ERLIN2
negative regulation of fatty acid biosynthetic process	1	887.0×	0.002	ERLIN2
cholesterol metabolic process	1	195.9×	0.006	ERLIN2
ERAD pathway	1	181.2×	0.006	ERLIN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERLIN2	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
ERLIN2	2	Binding:2

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	ERLIN2

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)
ERLIN2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.