Is RTN2 p.Arg395= (c.1185G>A) pathogenic?

RTN2 p.Arg395= (c.1185G>A) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-19). Very rare (popmax 0.000341%, nfe); Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Arg395= (c.1185G>A)?

RTN2 p.Arg395= (c.1185G>A) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Arg395= (c.1185G>A) in the general population?

RTN2 p.Arg395= (c.1185G>A) is very rare (popmax 0.000341%, 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.

RTN2 p.Arg395=

c.1185G>A · rs781104615 · VCV893821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.68, phastCons 1
Overall
CADD	14.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000341% European (non-Finnish) · 4/1,174,510 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00025% 4/1,601,334 alleles · very rare exomes 2/1,449,328 · genomes 2/152,006 · 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.Arg395=
Coding: c.1185G>A
MANE Select: NM_005619
dbSNP: rs781104615
Type: single nucleotide variant
Location: chr19:45489402 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 395: 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.Arg395Ser 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.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-arg395 (accessed [today's date]).

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