Is RTN2 p.Tyr495Cys (c.1484A>G) pathogenic?

RTN2 p.Tyr495Cys (c.1484A>G) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.9247); Very rare (popmax 0.0033%, sas); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Tyr495Cys (c.1484A>G)?

RTN2 p.Tyr495Cys (c.1484A>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Tyr495Cys (c.1484A>G) in the general population?

RTN2 p.Tyr495Cys (c.1484A>G) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about RTN2 p.Tyr495Cys (c.1484A>G)?

AlphaMissense predicts likely pathogenic (score 0.9247) — an in-silico prediction, not a clinical call.

RTN2 p.Tyr495Cys

c.1484A>G · rs1037969877 · VCV1343963

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9247	likely pathogenic · top 7% in RTN2
REVEL	0.741	pathogenic-leaning
SaProt	LLR -12.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% South Asian · 3/91,012 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,613,850 alleles · very rare exomes 5/1,461,640 · genomes 0/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,337
African / African-American	0.00133%	75,018
European (non-Finnish)	8.48e-05%	1,179,920

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.Tyr495Cys
Coding: c.1484A>G
MANE Select: NM_005619
dbSNP: rs1037969877
Type: single nucleotide variant
Location: chr19:45488484 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 495: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

Similar variants

RTN2 p.Arg406Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg496Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg85Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg91His Uncertain significance ★★ ⚠ same condition
RTN2 p.Asn177Ser Uncertain significance ★★ ⚠ same condition
RTN2 p.Asp418Glu Uncertain significance ★★ same condition
RTN2 p.Gln512Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu169Lys 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-tyr495cys (accessed [today's date]).

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