Is RTN2 p.Arg447Trp (c.1339C>T) pathogenic?

RTN2 p.Arg447Trp (c.1339C>T) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.4038); Very rare (popmax 0.00894%, sas); Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Arg447Trp (c.1339C>T)?

RTN2 p.Arg447Trp (c.1339C>T) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Arg447Trp (c.1339C>T) in the general population?

RTN2 p.Arg447Trp (c.1339C>T) is very rare (popmax 0.00894%, sas) (gnomAD).

How is Autosomal dominant spastic paraplegia type 12 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RTN2 p.Arg447Trp (c.1339C>T)?

AlphaMissense predicts ambiguous (score 0.4038) — an in-silico prediction, not a clinical call.

RTN2 p.Arg447Trp

c.1339C>T · rs764827191 · VCV893523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00894%, sas)

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
AlphaMissense	0.4038	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -11.63	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.65, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	32.0	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 0.00894% South Asian · 8/89,472 alleles

Filtering AF 0.00444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00317%

Overall 0.00125% 20/1,605,574 alleles · very rare exomes 19/1,453,340 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00894%	11,184
European (non-Finnish)	0.00102%	98,068

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.Arg447Trp
Coding: c.1339C>T
MANE Select: NM_005619
dbSNP: rs764827191
Type: single nucleotide variant
Location: chr19:45488889 (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

hereditary spastic paraplegia 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 12 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

RTN2 p.Arg447Gln 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.Leu394Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser441Leu Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser540Pro Uncertain significance ★★ ⚠ same condition
RTN2 p.Val471Met 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-arg447trp (accessed [today's date]).

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