ERLIN2

Chr 8ADAR

ER lipid raft associated 2

Also known as: C8orf2, Erlin-2, NET32, SPFH2, SPG18, SPG18A, SPG18B

NCBI Gene: 11160ENSG00000147475UniProt: O94905

This gene encodes a member of the SPFH domain-containing family of lipid raft-associated proteins. The encoded protein is localized to lipid rafts of the endoplasmic reticulum and plays a critical role in inositol 1,4,5-trisphosphate (IP3) signaling by mediating ER-associated degradation of activated IP3 receptors. Mutations in this gene are a cause of spastic paraplegia-18 (SPG18). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

Primary Disease Associations & Inheritance

Spastic paraplegia 18A, autosomal dominantMIM #620512
AD
Spastic paraplegia 18B, autosomal recessiveMIM #611225
AR
281
ClinVar variants
92
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ERLIN2
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia 18 · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
92 Pathogenic / Likely Pathogenic· 98 VUS of 281 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.83LOEUF
pLI 0.001
Z-score 2.08
OE 0.46 (0.27–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.88Z-score
OE missense 0.60 (0.52–0.71)
108 obs / 178.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.46 (0.27–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.52–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 8 / 17.3Missense obs/exp: 108 / 178.6Syn Z: 0.35

ClinVar Variant Classifications

281 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76
Likely Pathogenic16
VUS98
Likely Benign67
Benign15
Conflicting9
76
Pathogenic
16
Likely Pathogenic
98
VUS
67
Likely Benign
15
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
5
61
1
76
Likely Pathogenic
7
6
3
0
16
VUS
1
77
18
2
98
Likely Benign
0
0
33
34
67
Benign
0
0
13
2
15
Conflicting
—9
Total178812839281

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ERLIN2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ERLIN2-related intellectual developmental disorder

limited
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 18A, autosomal dominant

MIM #620512

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 18B, autosomal recessive

MIM #611225

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ERLIN2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CLPTM1L interacts with ERLIN2 to stabilize SREBP1 and drive tumorigenesis in nasopharyngeal carcinoma.
Zhang J et al.·Cell Death Dis
2025
KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1.
Xiao B et al.·Carcinogenesis
2023
A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family.
Wang J et al.·Ann Clin Transl Neurol
2023
Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models.
Zhu X et al.·Hum Mutat
2023Functional
A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.
Rydning SL et al.·Eur J Neurol
2018
Expansion of the genetic landscape of ERLIN2-related disorders.
Srivastava S et al.·Ann Clin Transl Neurol
2020
Novel ERLIN2 variant expands the phenotype of Spastic Paraplegia 18.
de Souza GC et al.·Neurol Sci
2024Case report
Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.
Trinchillo A et al.·Neurol Sci
2024
An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18).
Park JM et al.·Sci Rep
2020
Endoplasmic reticulum stress-related genes as prognostic and immunogenic biomarkers in prostate cancer.
Wan L et al.·Eur J Med Res
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools