Is ERLIN2 p.Ile84Val (c.250A>G) pathogenic?

ERLIN2 p.Ile84Val (c.250A>G) is classified Uncertain significance in ERLIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-24). AlphaMissense: likely pathogenic (0.5729); Very rare (popmax 8.48e-05%, nfe); Associated with Spastic paraplegia.

What condition is associated with ERLIN2 p.Ile84Val (c.250A>G)?

ERLIN2 p.Ile84Val (c.250A>G) is associated with Spastic paraplegia (ClinVar).

How common is ERLIN2 p.Ile84Val (c.250A>G) in the general population?

ERLIN2 p.Ile84Val (c.250A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERLIN2 p.Ile84Val (c.250A>G)?

AlphaMissense predicts likely pathogenic (score 0.5729) — an in-silico prediction, not a clinical call.

ERLIN2 p.Ile84Val

c.250A>G · rs1802961258 · VCV2975376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.5729	likely pathogenic
REVEL	0.531	indeterminate
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 6,689 bp · p 9.5e-05 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,179,880 alleles

Overall 6.84e-05% 1/1,461,738 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.Ile84Val
Coding: c.250A>G
MANE Select: NM_007175
dbSNP: rs1802961258
Type: single nucleotide variant
Location: chr8:37744368 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 5 PDB

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

Similar variants

ERLIN2 p.Ala151Val 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
ERLIN2 p.Gln154Pro Uncertain significance ★★ ⚠ same condition
ERLIN2 p.Gln63Arg 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-ile84val (accessed [today's date]).

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