Is RTN2 p.Thr428= (c.1284G>A) pathogenic?

RTN2 p.Thr428= (c.1284G>A) is classified Likely benign in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.064%, afr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Thr428= (c.1284G>A)?

RTN2 p.Thr428= (c.1284G>A) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Thr428= (c.1284G>A) in the general population?

RTN2 p.Thr428= (c.1284G>A) is ultra-rare (popmax 0.064%, afr) (gnomAD).

RTN2 p.Thr428=

c.1284G>A · rs150707032 · VCV2650113

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.064%, afr)

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 -8.3	GERP -3.6
Overall
CADD	2.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.064% African / African-American · 48/75,002 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.00441% 71/1,611,430 alleles · ultra-rare exomes 39/1,459,176 · genomes 32/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.064%	1,563
Middle Eastern	0.0165%	6,046
Remaining individualsnot grpmax-eligible	0.00641%	15,595
European (non-Finnish)	0.00153%	65,501

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.Thr428=
Coding: c.1284G>A
MANE Select: NM_005619
dbSNP: rs150707032
Type: single nucleotide variant
Location: chr19:45488944 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 428: 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.Thr428Lys Uncertain significance ★★ ⚠ same residue
RTN2 p.Thr428Met Uncertain significance ★ ⚠ same residue
RTN2 p.Thr428Ala Uncertain significance ★ ⚠ 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

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-thr428 (accessed [today's date]).

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