Is RTN2 p.Val379Met (c.1135G>A) pathogenic?

RTN2 p.Val379Met (c.1135G>A) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.5361); Ultra-rare (popmax 0.0706%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Val379Met (c.1135G>A)?

RTN2 p.Val379Met (c.1135G>A) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Val379Met (c.1135G>A) in the general population?

RTN2 p.Val379Met (c.1135G>A) is ultra-rare (popmax 0.0706%, sas) (gnomAD).

What do computational predictors say about RTN2 p.Val379Met (c.1135G>A)?

AlphaMissense predicts ambiguous (score 0.5361) — an in-silico prediction, not a clinical call.

RTN2 p.Val379Met

c.1135G>A · rs532500975 · VCV2140613

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5361 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0706%, sas)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.5361	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -11.58	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	28.3	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

Grpmax group 0.0706% South Asian · 64/90,658 alleles

Filtering AF 0.0567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0517%

Overall 0.00967% 156/1,612,440 alleles · ultra-rare exomes 145/1,460,496 · genomes 11/151,944 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0706%	1,417
Finnishnot grpmax-eligible	0.0219%	4,562
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.00801%	12,484
European (non-Finnish)	0.00577%	17,344
East Asian	0.00446%	22,412
Admixed American	0.00334%	29,915

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.Val379Met
Coding: c.1135G>A
MANE Select: NM_005619
dbSNP: rs532500975
Type: single nucleotide variant
Location: chr19:45489452 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 379: 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.Val379= Likely 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-val379met (accessed [today's date]).

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