Is ERLIN2 p.Leu41= (c.123G>A) pathogenic?

ERLIN2 p.Leu41= (c.123G>A) is classified Conflicting classifications of pathogenicity in ERLIN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-18). Rare (popmax 0.39%, afr); Associated with Spastic paraplegia.

What condition is associated with ERLIN2 p.Leu41= (c.123G>A)?

ERLIN2 p.Leu41= (c.123G>A) is associated with Spastic paraplegia (ClinVar).

How common is ERLIN2 p.Leu41= (c.123G>A) in the general population?

ERLIN2 p.Leu41= (c.123G>A) is rare (popmax 0.39%, afr) (gnomAD).

ERLIN2 p.Leu41=

c.123G>A · rs112575270 · VCV435086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.39%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	8.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.39% African / African-American · 292/74,926 alleles

Filtering AF 0.353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.339%

Overall 0.0234% 378/1,612,584 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.39%	257
Middle Eastern	0.0826%	1,210
Remaining individualsnot grpmax-eligible	0.0465%	2,151
Admixed American	0.0284%	3,527
European (non-Finnish)	0.00288%	34,681
South Asian	0.0011%	91,056

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.Leu41=
Coding: c.123G>A
MANE Select: NM_007175
dbSNP: rs112575270
Type: single nucleotide variant
Location: chr8:37740380 (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-leu41 (accessed [today's date]).

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