Is RTN2 p.Leu394Arg (c.1181T>G) pathogenic?

RTN2 p.Leu394Arg (c.1181T>G) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-01). AlphaMissense: likely pathogenic (0.5709); Very rare (popmax 0.00162%, nfe); Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Leu394Arg (c.1181T>G)?

RTN2 p.Leu394Arg (c.1181T>G) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Leu394Arg (c.1181T>G) in the general population?

RTN2 p.Leu394Arg (c.1181T>G) is very rare (popmax 0.00162%, nfe) (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.Leu394Arg (c.1181T>G)?

AlphaMissense predicts likely pathogenic (score 0.5709) — an in-silico prediction, not a clinical call.

RTN2 p.Leu394Arg

c.1181T>G · rs755919124 · VCV893822

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00162%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
AlphaMissense	0.5709	likely pathogenic
REVEL	0.509	indeterminate
SaProt	LLR -13.14	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	28.9	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 0.00162% European (non-Finnish) · 19/1,175,272 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00168% 27/1,603,008 alleles · very rare exomes 25/1,450,996 · genomes 2/152,012 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00805%	12,420
Finnishnot grpmax-eligible	0.00474%	21,079
European (non-Finnish)grpmax	0.00162%	61,856

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu394Arg
Coding: c.1181T>G
MANE Select: NM_005619
dbSNP: rs755919124
Type: single nucleotide variant
Location: chr19:45489406 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 394: 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.Leu394Val Uncertain significance ★ ⚠ same residue
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.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-leu394arg (accessed [today's date]).

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