Is RTN2 p.Ser32= (c.96T>C) pathogenic?

RTN2 p.Ser32= (c.96T>C) is classified Benign in RTN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 15.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ser32= (c.96T>C)?

RTN2 p.Ser32= (c.96T>C) is associated with Spastic paraplegia (ClinVar).

RTN2 p.Ser32=

Q: How common is RTN2 p.Ser32= (c.96T>C) in the general population?

RTN2 p.Ser32= (c.96T>C) is common (popmax 15.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.96T>C · rs10401270 · VCV130163

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 15.9%, eas) — too common for a highly-penetrant pathogenic allele

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 -11	GERP -3.6
Overall
CADD	3.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.9% East Asian · 7,149/44,856 alleles

Filtering AF 15.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.5%

Overall 11.7% 188,097/1,613,002 alleles · common exomes 169,544/1,460,814 · genomes 18,553/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	15.9%	6
South Asian	15.7%	6
Admixed American	15.6%	6
African / African-American	14%	7
Remaining individualsnot grpmax-eligible	12%	8
Finnishnot grpmax-eligible	11.9%	8
European (non-Finnish)	10.9%	9
Ashkenazi Jewishnot grpmax-eligible	10.2%	10
Middle Eastern	10%	10
Amishnot grpmax-eligible	0.548%	182

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.Ser32=
Coding: c.96T>C
MANE Select: NM_005619
dbSNP: rs10401270
Type: single nucleotide variant
Location: chr19:45494989 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 32: a UniProt-annotated variant site (in hmnr11; 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

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-ser32 (accessed [today's date]).

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