Is RTN2 p.Ala346= (c.1038G>A) pathogenic?

RTN2 p.Ala346= (c.1038G>A) is classified Likely benign in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). Very rare (popmax 0.00919%, eas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ala346= (c.1038G>A)?

RTN2 p.Ala346= (c.1038G>A) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Ala346= (c.1038G>A) in the general population?

RTN2 p.Ala346= (c.1038G>A) is very rare (popmax 0.00919%, eas) (gnomAD).

RTN2 p.Ala346=

c.1038G>A · VCV3719359

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00919%, 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 -1.2	GERP -3.3, phastCons 0.001
Overall
CADD	12.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00919% East Asian · 4/43,516 alleles

Filtering AF 0.00304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00184%

Overall 0.00201% 32/1,594,860 alleles · very rare exomes 29/1,442,762 · genomes 3/152,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00919%	10,879
European (non-Finnish)	0.00222%	45,043
Remaining individualsnot grpmax-eligible	0.00162%	61,808
South Asian	0.00114%	87,856

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.Ala346=
Coding: c.1038G>A
MANE Select: NM_005619
Type: single nucleotide variant
Location: chr19:45489549 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 346: 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.Ala346Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala346 (accessed [today's date]).

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