Is RTN2 p.Arg425Trp (c.1273C>T) pathogenic?

RTN2 p.Arg425Trp (c.1273C>T) is classified Likely benign in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.2458); Rare (popmax 0.17%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Arg425Trp (c.1273C>T)?

RTN2 p.Arg425Trp (c.1273C>T) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Arg425Trp (c.1273C>T) in the general population?

RTN2 p.Arg425Trp (c.1273C>T) is rare (popmax 0.17%, sas) (gnomAD).

What do computational predictors say about RTN2 p.Arg425Trp (c.1273C>T)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

RTN2 p.Arg425Trp

c.1273C>T · rs147161725 · VCV2193792

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.17%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -10.91	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.7, phastCons 0.54
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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.17% South Asian · 154/90,464 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.14%

Overall 0.0123% 199/1,611,656 alleles · rare exomes 174/1,459,350 · genomes 25/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.17%	587
African / African-American	0.0267%	3,750
Remaining individualsnot grpmax-eligible	0.00801%	12,482
Admixed American	0.00502%	19,902
East Asian	0.00223%	44,794
European (non-Finnish)	0.00136%	73,692

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.Arg425Trp
Coding: c.1273C>T
MANE Select: NM_005619
dbSNP: rs147161725
Type: single nucleotide variant
Location: chr19:45488955 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 425: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); a UniProt-annotated variant site (in); 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.Arg425Gln Benign/Likely benign ★★ same residue
RTN2 p.Arg425Pro 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-arg425trp (accessed [today's date]).

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