Is RTN2 p.Ser224= (c.672G>A) pathogenic?

RTN2 p.Ser224= (c.672G>A) is classified Benign/Likely benign in RTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-21). Rare (popmax 0.257%, sas); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ser224= (c.672G>A)?

RTN2 p.Ser224= (c.672G>A) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Ser224= (c.672G>A) in the general population?

RTN2 p.Ser224= (c.672G>A) is rare (popmax 0.257%, sas) (gnomAD).

RTN2 p.Ser224=

c.672G>A · rs377094463 · VCV697711

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.257%, sas)

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 -2.5	GERP -3.5
Overall
CADD	0.457	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.257% South Asian · 234/91,082 alleles

Filtering AF 0.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.219%

Overall 0.0198% 319/1,614,068 alleles · rare exomes 299/1,461,836 · genomes 20/152,232 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.257%	389
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)	0.00466%	21,455

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.Ser224=
Coding: c.672G>A
MANE Select: NM_005619
dbSNP: rs377094463
Type: single nucleotide variant
Location: chr19:45494308 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 224: 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

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

Also linked: hereditary spastic paraplegia

Similar variants

RTN2 p.Ser224Leu 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
RTN2 p.Arg398Cys 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-ser224 (accessed [today's date]).

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