Is RTN2 p.Pro492= (c.1476C>G) pathogenic?

RTN2 p.Pro492= (c.1476C>G) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-22). Very rare (popmax 0.00449%, nfe); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Pro492= (c.1476C>G)?

RTN2 p.Pro492= (c.1476C>G) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Pro492= (c.1476C>G) in the general population?

RTN2 p.Pro492= (c.1476C>G) is very rare (popmax 0.00449%, nfe) (gnomAD).

RTN2 p.Pro492=

c.1476C>G · rs748824542 · VCV805277

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.11	GERP -3.3, phastCons 0.045
Overall
CADD	2.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00449% European (non-Finnish) · 53/1,179,964 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00347% 56/1,613,844 alleles · very rare exomes 54/1,461,664 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,263
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00133%	74,914

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.Pro492=
Coding: c.1476C>G
MANE Select: NM_005619
dbSNP: rs748824542
Type: single nucleotide variant
Location: chr19:45488492 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 492: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the reticulon domain

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

Also linked: hereditary spastic paraplegia

Similar variants

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
RTN2 p.Arg496Trp 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-pro492 (accessed [today's date]).

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