ERLIN2

Chr 8ADAR

ER lipid raft associated 2

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

NCBI Gene: 11160 ENSG00000147475 UniProt: O94905 OMIM: 611605

This protein localizes to endoplasmic reticulum lipid rafts and mediates ER-associated degradation of inositol 1,4,5-trisphosphate receptors, playing a critical role in IP3 signaling and cellular cholesterol homeostasis. Mutations cause spastic paraplegia type 18, which can be inherited in either autosomal dominant (SPG18A) or autosomal recessive (SPG18B) patterns. The gene is not highly constrained against loss-of-function variants, suggesting that different types of mutations may underlie the distinct inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.832 OMIM phenotypes

Clinical Summary— ERLIN2

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia 18 · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 93 VUS of 227 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ERLIN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.001

Z-score 2.08

OE 0.46 (0.27–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.88Z-score

OE missense 0.60 (0.52–0.71)

108 obs / 178.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.27–0.83)

0≤0.351.4

Missense OE?0.60 (0.52–0.71)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 8 / 17.3Missense obs/exp: 108 / 178.6Syn Z: 0.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongERLIN2-related complex hereditary spastic paraplegia (HSP)LOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.82top 10%

GOF

0.6346th %ile

LOF

0.2484th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic15

VUS93

Likely Benign67

Benign15

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	5	0	1	20
Likely Pathogenic	8	7	0	0	15
VUS	1	81	9	2	93
Likely Benign	0	0	33	34	67
Benign	0	0	13	2	15
Conflicting	—				9
Total	23	93	55	39	219

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap ERLIN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →