Is ERLIN2 p.Leu185= (c.553T>C) pathogenic?

ERLIN2 p.Leu185= (c.553T>C) is classified Likely benign in ERLIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-15). Ultra-rare (popmax 0.0824%, sas); Associated with Spastic paraplegia.

What condition is associated with ERLIN2 p.Leu185= (c.553T>C)?

ERLIN2 p.Leu185= (c.553T>C) is associated with Spastic paraplegia (ClinVar).

How common is ERLIN2 p.Leu185= (c.553T>C) in the general population?

ERLIN2 p.Leu185= (c.553T>C) is ultra-rare (popmax 0.0824%, sas) (gnomAD).

ERLIN2 p.Leu185=

c.553T>C · rs150529140 · VCV1919265

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0824%, sas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.6	GERP -5.4
Overall
CADD	4.901	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0824% South Asian · 75/91,064 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0618%

Overall 0.0242% 390/1,613,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0824%	1,214
Remaining individualsnot grpmax-eligible	0.0272%	3,676
Admixed American	0.025%	3,998
European (non-Finnish)	0.0239%	4,184
African / African-American	0.00133%	74,920

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.Leu185=
Coding: c.553T>C
MANE Select: NM_007175
dbSNP: rs150529140
Type: single nucleotide variant
Location: chr8:37749848 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 5 PDB
Residue 185: 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

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-leu185 (accessed [today's date]).

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