Is RTN2 p.Glu95= (c.285A>G) pathogenic?

RTN2 p.Glu95= (c.285A>G) is classified Benign in RTN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-25). Low-frequency (popmax 1.27%, afr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Glu95= (c.285A>G)?

RTN2 p.Glu95= (c.285A>G) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Glu95= (c.285A>G) in the general population?

RTN2 p.Glu95= (c.285A>G) is low-frequency (popmax 1.27%, afr) (gnomAD).

RTN2 p.Glu95=

c.285A>G · rs146004780 · VCV448175

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, 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 -0.75	GERP -0.22, phastCons 0.022
Overall
CADD	8.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.27% African / African-American · 956/75,048 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.18%

Overall 0.0662% 1,062/1,604,526 alleles · low-frequency exomes 531/1,452,240 · genomes 531/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.27%	79
Remaining individualsnot grpmax-eligible	0.0993%	1,007
Admixed American	0.0467%	2,143
Middle Eastern	0.0165%	6,058
South Asian	0.00549%	18,215
European (non-Finnish)	0.000848%	117,986

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: RTN2
Protein: p.Glu95=
Coding: c.285A>G
MANE Select: NM_005619
dbSNP: rs146004780
Type: single nucleotide variant
Location: chr19:45494800 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 95: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the 'disordered' region

Full RTN2 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

RTN2 p.Glu95Lys Uncertain significance ★ ⚠ same residue
RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A Uncertain significance ★★ same condition
RTN2 p.Ala529Thr Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg152Pro Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg252Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg398Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg447Gln 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/rtn2-p-glu95 (accessed [today's date]).

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