Is RTN2 p.Ile520Met (c.1560C>G) pathogenic?

RTN2 p.Ile520Met (c.1560C>G) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.504); Ultra-rare (popmax 0.01%, amr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ile520Met (c.1560C>G)?

RTN2 p.Ile520Met (c.1560C>G) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Ile520Met (c.1560C>G) in the general population?

RTN2 p.Ile520Met (c.1560C>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about RTN2 p.Ile520Met (c.1560C>G)?

AlphaMissense predicts ambiguous (score 0.504) — an in-silico prediction, not a clinical call.

RTN2 p.Ile520Met

c.1560C>G · rs1159296807 · VCV2768298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.504 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.504	ambiguous
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.89, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	20.9	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 0.01% Admixed American · 6/59,984 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,613,436 alleles · ultra-rare exomes 5/1,461,294 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,997
European (non-Finnish)	8.48e-05%	1,179,540

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.Ile520Met
Coding: c.1560C>G
MANE Select: NM_005619
dbSNP: rs1159296807
Type: single nucleotide variant
Location: chr19:45485786 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 520: 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.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-ile520met (accessed [today's date]).

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