Is ERLIN2 p.Asp300Val (c.899A>T) pathogenic?

ERLIN2 p.Asp300Val (c.899A>T) is classified Conflicting classifications of pathogenicity in ERLIN2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-12-31). AlphaMissense: ambiguous (0.4159); Very rare (popmax 0.00246%, nfe); Associated with Spastic paraplegia.

What condition is associated with ERLIN2 p.Asp300Val (c.899A>T)?

ERLIN2 p.Asp300Val (c.899A>T) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is ERLIN2 p.Asp300Val (c.899A>T) in the general population?

ERLIN2 p.Asp300Val (c.899A>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about ERLIN2 p.Asp300Val (c.899A>T)?

AlphaMissense predicts ambiguous (score 0.4159) — an in-silico prediction, not a clinical call.

ERLIN2 p.Asp300Val

c.899A>T · rs763958615 · VCV424656

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4159	ambiguous
REVEL	0.362	indeterminate
SaProt	LLR -10.52	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 9,452 bp · p 1e-10 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,179,906 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,613,828 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERLIN2
Protein: p.Asp300Val
Coding: c.899A>T
MANE Select: NM_007175
dbSNP: rs763958615
Type: single nucleotide variant
Location: chr8:37753994 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 5 PDB
Residue 300: a UniProt-annotated variant site (in spg18b; uncertain significance); the 'interaction with erlin1' region

Full ERLIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

Similar variants

ERLIN2 p.Asp300Gly Uncertain significance ★★ ⚠ same residue
ERLIN2 p.Ala151Val Pathogenic/Likely pathogenic ★★ same condition
ERLIN2 p.Gln63Lys Pathogenic/Likely pathogenic ★★ same condition
ERLIN2 c.298+5G>A Uncertain significance ★★ same condition
ERLIN2 c.819+3A>G Uncertain significance ★★ same condition
ERLIN2 p.Ala290Val Uncertain significance ★★ ⚠ same condition
ERLIN2 p.Ala99Thr Uncertain significance ★★ ⚠ same condition
ERLIN2 p.Asn93Asp Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erlin2-p-asp300val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown