Is RTN2 p.Arg447Gln (c.1340G>A) pathogenic?

RTN2 p.Arg447Gln (c.1340G>A) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.1824); Very rare (popmax 0.00345%, amr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Arg447Gln (c.1340G>A)?

RTN2 p.Arg447Gln (c.1340G>A) is associated with Spastic paraplegia, hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Arg447Gln (c.1340G>A) in the general population?

RTN2 p.Arg447Gln (c.1340G>A) is very rare (popmax 0.00345%, amr) (gnomAD).

What do computational predictors say about RTN2 p.Arg447Gln (c.1340G>A)?

AlphaMissense predicts likely benign (score 0.1824) — an in-silico prediction, not a clinical call.

RTN2 p.Arg447Gln

c.1340G>A · rs1262346281 · VCV1445728

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00345%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1824	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00345% Admixed American · 2/57,966 alleles

Filtering AF 0.000572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.000436% 7/1,605,402 alleles · very rare exomes 6/1,453,194 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00345%	28,983
African / African-American	0.00267%	37,433
European (non-Finnish)	0.000255%	392,241

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.Arg447Gln
Coding: c.1340G>A
MANE Select: NM_005619
dbSNP: rs1262346281
Type: single nucleotide variant
Location: chr19:45488888 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 447: 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 12

Similar variants

RTN2 p.Arg447Trp Uncertain significance ★ same residue
RTN2 p.Arg447= Likely benign ★ 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-arg447gln (accessed [today's date]).

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