Is RTN2 p.Arg406Pro (c.1217G>C) pathogenic?

RTN2 p.Arg406Pro (c.1217G>C) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.4794); Ultra-rare (popmax 0.0642%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Arg406Pro (c.1217G>C)?

RTN2 p.Arg406Pro (c.1217G>C) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Arg406Pro (c.1217G>C) in the general population?

RTN2 p.Arg406Pro (c.1217G>C) is ultra-rare (popmax 0.0642%, sas) (gnomAD).

What do computational predictors say about RTN2 p.Arg406Pro (c.1217G>C)?

AlphaMissense predicts ambiguous (score 0.4794) — an in-silico prediction, not a clinical call.

RTN2 p.Arg406Pro

c.1217G>C · rs369158895 · VCV1148482

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0642%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4794	ambiguous
REVEL	0.243	benign-leaning
SaProt	LLR -10.27	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	23.9	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 0.0642% South Asian · 55/85,680 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0457%

Overall 0.00445% 70/1,574,558 alleles · ultra-rare exomes 65/1,422,460 · genomes 5/152,098 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0642%	1,558
African / African-American	0.00135%	74,152
European (non-Finnish)	0.00121%	82,904

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.Arg406Pro
Coding: c.1217G>C
MANE Select: NM_005619
dbSNP: rs369158895
Type: single nucleotide variant
Location: chr19:45489370 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 406: 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.Arg406Trp Uncertain significance ★★ ⚠ same residue
RTN2 p.Arg406Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg406pro (accessed [today's date]).

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