Is RTN2 p.Asp408fs (c.1222del) pathogenic?

RTN2 p.Asp408fs (c.1222del) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-12). Very rare (popmax 0.000259%, nfe).

How common is RTN2 p.Asp408fs (c.1222del) in the general population?

RTN2 p.Asp408fs (c.1222del) is very rare (popmax 0.000259%, nfe) (gnomAD).

RTN2 p.Asp408fs

c.1222del · VCV4083245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000259% European (non-Finnish) · 3/1,157,466 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000255% 4/1,568,768 alleles · very rare exomes 4/1,417,042 · genomes 0/151,726 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00164%	60,974
European (non-Finnish)grpmax	0.000259%	385,822

Finnish 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.Asp408fs
Coding: c.1222del
MANE Select: NM_005619
Type: Deletion
Location: chr19:45489365 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 408: 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

Similar variants

RTN2 p.Gly309fs Pathogenic/Likely pathogenic ★★ same type
RTN2 p.Gly57fs Pathogenic/Likely pathogenic ★★ same type
RTN2 c.1381-12del Benign/Likely benign ★★ same type
RTN2 p.Leu385fs Likely pathogenic ★ same type
RTN2 c.818_828del Conflicting classifications of pathogenicity ★ same type
RTN2 p.Arg91fs Uncertain significance ★ same type
RTN2 p.Glu158fs Uncertain significance ★ same type
RTN2 p.Thr314fs Conflicting classifications of pathogenicity ★ same type

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-asp408fs (accessed [today's date]).

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