Is ERLIN2 p.Gln63Pro (c.188A>C) pathogenic?

ERLIN2 p.Gln63Pro (c.188A>C) is classified Uncertain significance in ERLIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-12-12). AlphaMissense: likely pathogenic (0.9594); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia.

What condition is associated with ERLIN2 p.Gln63Pro (c.188A>C)?

ERLIN2 p.Gln63Pro (c.188A>C) is associated with hereditary spastic paraplegia (ClinVar).

How common is ERLIN2 p.Gln63Pro (c.188A>C) in the general population?

ERLIN2 p.Gln63Pro (c.188A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERLIN2 p.Gln63Pro (c.188A>C)?

AlphaMissense predicts likely pathogenic (score 0.9594) — an in-silico prediction, not a clinical call.

ERLIN2 p.Gln63Pro

c.188A>C · rs2129653824 · VCV1344328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9594 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9594	likely pathogenic
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -12.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.62	donor loss · deltas
Pangolin	Δ0.35	loss · gain 0.11 · agrees with SpliceAI · independent
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	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERLIN2
Protein: p.Gln63Pro
Coding: c.188A>C
MANE Select: NM_007175
dbSNP: rs2129653824
Type: single nucleotide variant
Location: chr8:37740445 (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

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

Similar variants

ERLIN2 p.Gln63Lys Pathogenic/Likely pathogenic ★★ same residue
ERLIN2 p.Gln63Arg Uncertain significance ★★ ⚠ same residue
ERLIN2 p.Val136Ile Uncertain significance ★★ ⚠ same condition
ERLIN2 p.Asn106= Benign ★★ same condition
ERLIN2 p.Lys232= Benign/Likely benign ★★ same condition
ERLIN2 p.Asn125Ser Pathogenic ★ same condition
ERLIN2 p.Ile144Val Pathogenic ★ ⚠ same condition
ERLIN2 p.Asp300Val Conflicting classifications of pathogenicity ★ 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-gln63pro (accessed [today's date]).

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