Is RTN2 p.Arg60fs (c.178dup) pathogenic?

RTN2 p.Arg60fs (c.178dup) is classified Pathogenic in RTN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2012-02-01). Very rare (popmax 0.00133%, afr); Associated with neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity.

How common is RTN2 p.Arg60fs (c.178dup) in the general population?

RTN2 p.Arg60fs (c.178dup) is very rare (popmax 0.00133%, afr) (gnomAD).

RTN2 p.Arg60fs

Q: What condition is associated with RTN2 p.Arg60fs (c.178dup)?

RTN2 p.Arg60fs (c.178dup) is associated with neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity, hereditary spastic paraplegia 12 (ClinVar).

c.178dup · rs763387041 · VCV30324

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

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 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	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 0.00133% African / African-American · 1/75,034 alleles

Overall 0.000186% 3/1,612,650 alleles · very rare exomes 3/1,460,378 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0016%	62,582
African / African-Americangrpmax	0.00133%	75,034
European (non-Finnish)	8.47e-05%	1,180,004

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.Arg60fs
Coding: c.178dup
MANE Select: NM_005619
dbSNP: rs763387041
Type: Duplication
Location: chr19:45494906 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 60: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the 'disordered' region

Full RTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 12

Similar variants

RTN2 p.Arg60Trp Uncertain significance ★ ⚠ same residue
RTN2 p.Arg60= Likely benign ★ same residue
RTN2 p.Leu235fs Pathogenic same condition
RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 p.Gly309fs Pathogenic/Likely pathogenic ★★ same condition
RTN2 p.Gly57fs Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A 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-arg60fs (accessed [today's date]).

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