Is RTN2 p.Leu368Phe (c.1102C>T) pathogenic?

RTN2 p.Leu368Phe (c.1102C>T) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely pathogenic (0.7003); Very rare (popmax 0.00882%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Leu368Phe (c.1102C>T)?

RTN2 p.Leu368Phe (c.1102C>T) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Leu368Phe (c.1102C>T) in the general population?

RTN2 p.Leu368Phe (c.1102C>T) is very rare (popmax 0.00882%, sas) (gnomAD).

What do computational predictors say about RTN2 p.Leu368Phe (c.1102C>T)?

AlphaMissense predicts likely pathogenic (score 0.7003) — an in-silico prediction, not a clinical call.

RTN2 p.Leu368Phe

c.1102C>T · VCV3704016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00882%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.7003	likely pathogenic
REVEL	0.459	indeterminate
SaProt	LLR -11.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00882% South Asian · 8/90,724 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.000496% 8/1,612,860 alleles · very rare exomes 8/1,460,758 · genomes 0/152,102 · joint denominator

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.Leu368Phe
Coding: c.1102C>T
MANE Select: NM_005619
Type: single nucleotide variant
Location: chr19:45489485 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 368: 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.Leu368= 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
RTN2 p.Arg447Gln 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-leu368phe (accessed [today's date]).

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