Is ERLIN2 p.Arg253Gln (c.758G>A) pathogenic?

ERLIN2 p.Arg253Gln (c.758G>A) is classified Uncertain significance in ERLIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-28). AlphaMissense: likely benign (0.1671); Very rare (popmax 0.00223%, eas); Associated with Spastic paraplegia.

What condition is associated with ERLIN2 p.Arg253Gln (c.758G>A)?

ERLIN2 p.Arg253Gln (c.758G>A) is associated with Spastic paraplegia (ClinVar).

How common is ERLIN2 p.Arg253Gln (c.758G>A) in the general population?

ERLIN2 p.Arg253Gln (c.758G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERLIN2 p.Arg253Gln (c.758G>A)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

ERLIN2 p.Arg253Gln

c.758G>A · rs1235728999 · VCV2187738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 9,452 bp · p 1e-10 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
European (non-Finnish)	0.000339%	295,002

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.Arg253Gln
Coding: c.758G>A
MANE Select: NM_007175
dbSNP: rs1235728999
Type: single nucleotide variant
Location: chr8:37753468 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 5 PDB
Residue 253: 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-arg253gln (accessed [today's date]).

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