Is RTN2 p.Ile474Thr (c.1421T>C) pathogenic?

RTN2 p.Ile474Thr (c.1421T>C) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.5618); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Ile474Thr (c.1421T>C)?

RTN2 p.Ile474Thr (c.1421T>C) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Ile474Thr (c.1421T>C) in the general population?

RTN2 p.Ile474Thr (c.1421T>C) is absent from gnomAD v4.1 (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.Ile474Thr (c.1421T>C)?

AlphaMissense predicts ambiguous (score 0.5618) — an in-silico prediction, not a clinical call.

RTN2 p.Ile474Thr

c.1421T>C · rs1968080913 · VCV893522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5618 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
AlphaMissense	0.5618	ambiguous
REVEL	0.123	moderately benign-leaning
SaProt	LLR -9.30	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RTN2
Protein: p.Ile474Thr
Coding: c.1421T>C
MANE Select: NM_005619
dbSNP: rs1968080913
Type: single nucleotide variant
Location: chr19:45488666 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 474: 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.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A Uncertain significance ★★ same condition
RTN2 p.Arg447Gln 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
RTN2 p.Val485Met 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-ile474thr (accessed [today's date]).

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