Is RTN2 p.Arg496Trp (c.1486C>T) pathogenic?

RTN2 p.Arg496Trp (c.1486C>T) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-30). AlphaMissense: ambiguous (0.4758); Ultra-rare (popmax 0.0165%, mid); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Arg496Trp (c.1486C>T)?

RTN2 p.Arg496Trp (c.1486C>T) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Arg496Trp (c.1486C>T) in the general population?

RTN2 p.Arg496Trp (c.1486C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about RTN2 p.Arg496Trp (c.1486C>T)?

AlphaMissense predicts ambiguous (score 0.4758) — an in-silico prediction, not a clinical call.

RTN2 p.Arg496Trp

c.1486C>T · rs199848753 · VCV2267266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4758 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4758	ambiguous
REVEL	0.227	benign-leaning
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP -0.67, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00316% 51/1,613,836 alleles · ultra-rare exomes 48/1,461,588 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.005%	19,992
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00339%	29,498
African / African-American	0.00267%	37,514
Finnishnot grpmax-eligible	0.00156%	64,028
South Asian	0.0011%	91,004

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.Arg496Trp
Coding: c.1486C>T
MANE Select: NM_005619
dbSNP: rs199848753
Type: single nucleotide variant
Location: chr19:45488482 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 496: 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

Similar variants

RTN2 p.Arg496Leu Uncertain significance ★ ⚠ same residue
RTN2 p.Arg496Gln 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

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-arg496trp (accessed [today's date]).

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