Is RTN2 p.Arg35Ter (c.103C>T) pathogenic?

RTN2 p.Arg35Ter (c.103C>T) is classified Pathogenic in RTN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-01). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Arg35Ter (c.103C>T)?

RTN2 p.Arg35Ter (c.103C>T) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Arg35Ter (c.103C>T) in the general population?

RTN2 p.Arg35Ter (c.103C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Autosomal dominant spastic paraplegia type 12 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

RTN2 p.Arg35Ter

c.103C>T · rs1968243327 · VCV3248640

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 0.67, phastCons 1
Overall
CADD	53.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,458 alleles

Overall 6.2e-05% 1/1,613,372 alleles · very rare exomes 1/1,461,054 · genomes 0/152,318 · joint denominator

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.Arg35Ter
Coding: c.103C>T
MANE Select: NM_005619
dbSNP: rs1968243327
Type: single nucleotide variant
Location: chr19:45494982 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 35: 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

hereditary spastic paraplegia 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 12 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A Uncertain significance ★★ same condition
RTN2 p.Arg447Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Leu394Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser441Leu Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser540Pro Uncertain significance ★★ ⚠ same condition
RTN2 p.Val471Met Uncertain significance ★★ same condition
RTN2 p.Val485Met 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-arg35ter (accessed [today's date]).

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