Is RTN2 p.Arg85Cys (c.253C>T) pathogenic?

RTN2 p.Arg85Cys (c.253C>T) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-29). AlphaMissense: ambiguous (0.408); Very rare (popmax 0.0011%, nfe); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Arg85Cys (c.253C>T)?

RTN2 p.Arg85Cys (c.253C>T) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Arg85Cys (c.253C>T) in the general population?

RTN2 p.Arg85Cys (c.253C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about RTN2 p.Arg85Cys (c.253C>T)?

AlphaMissense predicts ambiguous (score 0.408) — an in-silico prediction, not a clinical call.

RTN2 p.Arg85Cys

c.253C>T · rs751101450 · VCV1343965

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.408	ambiguous
REVEL	0.169	moderately benign-leaning
SaProt	LLR -8.85	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,802 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000936% 15/1,603,406 alleles · very rare exomes 14/1,451,238 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00186%	53,770
Remaining individualsnot grpmax-eligible	0.0016%	62,394
European (non-Finnish)grpmax	0.0011%	90,754

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg85Cys
Coding: c.253C>T
MANE Select: NM_005619
dbSNP: rs751101450
Type: single nucleotide variant
Location: chr19:45494832 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 85: 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.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-arg85cys (accessed [today's date]).

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