Is RTN2 p.Thr314fs (c.939del) pathogenic?

RTN2 p.Thr314fs (c.939del) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0275%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Thr314fs (c.939del)?

RTN2 p.Thr314fs (c.939del) is associated with Spastic paraplegia, hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Thr314fs (c.939del) in the general population?

RTN2 p.Thr314fs (c.939del) is ultra-rare (popmax 0.0275%, sas) (gnomAD).

RTN2 p.Thr314fs

c.939del · rs768449676 · VCV378054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Conditions

Spastic paraplegia

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 5 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9	GERP -3.6
Overall
CADD	16.97	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 0.0275% South Asian · 25/90,988 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.0057% 92/1,612,998 alleles · ultra-rare exomes 83/1,461,066 · genomes 9/151,932 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,640
European (non-Finnish)	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.0048%	20,820
East Asian	0.00446%	22,405
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
African / African-American	0.00267%	37,421

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.Thr314fs
Coding: c.939del
MANE Select: NM_005619
dbSNP: rs768449676
Type: Deletion
Location: chr19:45493254 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 314: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic)

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

Also linked: hereditary spastic paraplegia 12

Similar variants

RTN2 p.Gly309fs Pathogenic/Likely pathogenic ★★ same condition
RTN2 p.Gly57fs Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1381-12del Benign/Likely benign ★★ same condition
RTN2 c.818_828del Conflicting classifications of pathogenicity ★ same condition
RTN2 c.560-7del Likely benign ★ same condition
RTN2 p.Thr314Ile Likely benign ★ same residue
RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A 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-thr314fs (accessed [today's date]).

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