Is RTN2 p.Ser378= (c.1134C>T) pathogenic?

RTN2 p.Ser378= (c.1134C>T) is classified Likely benign in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). Ultra-rare (popmax 0.0513%, eas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ser378= (c.1134C>T)?

RTN2 p.Ser378= (c.1134C>T) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Ser378= (c.1134C>T) in the general population?

RTN2 p.Ser378= (c.1134C>T) is ultra-rare (popmax 0.0513%, eas) (gnomAD).

RTN2 p.Ser378=

c.1134C>T · rs202061449 · VCV2995052

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.6
Overall
CADD	3.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0513% East Asian · 23/44,830 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0297%

Overall 0.0018% 29/1,612,554 alleles · ultra-rare exomes 26/1,460,492 · genomes 3/152,062 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,949
Admixed American	0.00167%	59,846
South Asian	0.0011%	90,688
European (non-Finnish)	0.000339%	294,854

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.Ser378=
Coding: c.1134C>T
MANE Select: NM_005619
dbSNP: rs202061449
Type: single nucleotide variant
Location: chr19:45489453 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 378: 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.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
RTN2 p.Arg496Trp 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-ser378 (accessed [today's date]).

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