Is RTN2 p.Thr444= (c.1332G>A) pathogenic?

RTN2 p.Thr444= (c.1332G>A) is classified Likely benign in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). Very rare (popmax 0.00171%, amr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Thr444= (c.1332G>A)?

RTN2 p.Thr444= (c.1332G>A) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Thr444= (c.1332G>A) in the general population?

RTN2 p.Thr444= (c.1332G>A) is very rare (popmax 0.00171%, amr) (gnomAD).

RTN2 p.Thr444=

c.1332G>A · rs149504512 · VCV1133365

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

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 -4.9	GERP -3.6
Overall
CADD	1.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00171% Admixed American · 1/58,394 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000498% 8/1,606,878 alleles · very rare exomes 8/1,454,546 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,394
Remaining individualsnot grpmax-eligible	0.00161%	62,266
South Asian	0.00112%	89,608
European (non-Finnish)	0.000425%	235,459

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.Thr444=
Coding: c.1332G>A
MANE Select: NM_005619
dbSNP: rs149504512
Type: single nucleotide variant
Location: chr19:45488896 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 444: 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.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
RTN2 p.Arg398Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg447Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg496Trp 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-thr444 (accessed [today's date]).

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