# NM_007175.8(ERLIN2):c.988del (p.Glu330fs)

https://sugi.bio/variant/erlin2-p-glu330fs

## Summary

**ERLIN2 p.Glu330fs (c.988del)** is classified **Likely pathogenic** in ERLIN2 (ClinVar, Single submitter, 1 submitter). Associated with spastic paraplegia 18b, autosomal recessive.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the ERLIN2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to spastic paraplegia 18b, autosomal recessive.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | ERLIN2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Autosomal spastic paraplegia type 18** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- Distal muscle weakness — Very frequent (99-80%)
- Inability to walk — Very frequent (99-80%)
- Elbow flexion contracture — Very frequent (99-80%)
- Knee flexion contracture — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028012/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERLIN2](https://sugi.bio/atlas/gene/ERLIN2/) |
| Protein change (HGVS p.) | p.Glu330fs |
| Coding change (HGVS c.) | c.988del |
| MANE Select transcript | [NM_007175](https://www.ncbi.nlm.nih.gov/nuccore/NM_007175) |
| Variant type | Deletion |
| Location | chr8:37754083-37754083 (GRCh38) |
| ClinVar | [VCV4759352](https://www.ncbi.nlm.nih.gov/clinvar/variation/4759352/) |

**All HGVS expressions:** `LRG_1040:g.22505del`, `LRG_1040t2:c.988del`, `NC_000008.10:g.37611601del`, `NC_000008.11:g.37754083del`, `NG_032059.1:g.22505del`, `NM_001362878.2:c.988del`, `NM_007175.8:c.988del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -4.26, GERP -5.2 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.703, pLI 0.010039. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (12 of 12)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ERLIN2** population constraint: LOEUF 0.703, pLI 0.010039, missense-Z 3.3092. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary spastic paraplegia 18** — Limited (AD)
- **hereditary spastic paraplegia 18** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.35, 70% of residues very-high.

**5 experimental structure(s)** (PDB): [9O9U](https://www.rcsb.org/structure/9O9U), [9VVG](https://www.rcsb.org/structure/9VVG), [9VVJ](https://www.rcsb.org/structure/9VVJ), [9WE7](https://www.rcsb.org/structure/9WE7), [9WFF](https://www.rcsb.org/structure/9WFF).

## What this gene does {#gene-function}

*Describes the biological roles of ERLIN2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ERLIN2's established molecular role includes ubiquitin protein ligase binding. In Reactome, ERLIN2 is annotated in disease pathway(s) including **Defective CFTR causes cystic fibrosis**, **Signaling by FGFR1 in disease**.

**Disease mechanism (Reactome):** ERLIN2 loss or alteration is curated in [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895), [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302), [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336).

### Pathways affected {#pathways}

ERLIN2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | curated |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin protein ligase binding.

**Biological process:** SREBP signaling pathway, ERAD pathway, regulation of cholesterol biosynthetic process, negative regulation of cholesterol biosynthetic process, negative regulation of fatty acid biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences | Likely pathogenic | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

[spastic paraplegia 18b, autosomal recessive](https://sugi.bio/atlas/disease/spastic-paraplegia-18b-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Spastic paraplegia 18b, autosomal recessive, INTELLECTUAL DISABILITY, MOTOR DYSFUNCTION, AND JOINT CONTRACTURES.

## Similar variants {#similar}

Related ERLIN2 variant pages (same residue, condition, or type): [ERLIN2 c.819+2T>C](/variant/erlin2-c-819-plus-2t-c), [ERLIN2 p.Glu184Lys](/variant/erlin2-p-glu184lys), [ERLIN2 p.Ser324fs](/variant/erlin2-p-ser324fs), [ERLIN2 p.Ala335_Thr336del](/variant/erlin2-p-ala335-thr336del), [ERLIN2 p.Ala6fs](/variant/erlin2-p-ala6fs), [ERLIN2 p.Asn118fs](/variant/erlin2-p-asn118fs), [ERLIN2 p.Asn182_Tyr183insTer](/variant/erlin2-p-asn182-tyr183inster), [ERLIN2 p.Cys16fs](/variant/erlin2-p-cys16fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4759352). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*