Is RTN2 p.Cys255Phe (c.764G>T) pathogenic?

RTN2 p.Cys255Phe (c.764G>T) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-06). AlphaMissense: likely benign (0.1554); Very rare (popmax 0.000847%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with RTN2 p.Cys255Phe (c.764G>T)?

RTN2 p.Cys255Phe (c.764G>T) is associated with hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Cys255Phe (c.764G>T) in the general population?

RTN2 p.Cys255Phe (c.764G>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about RTN2 p.Cys255Phe (c.764G>T)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

RTN2 p.Cys255Phe

c.764G>T · rs775281770 · VCV1343968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000847% European (non-Finnish) · 10/1,180,002 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000621% 10/1,610,202 alleles · very rare exomes 10/1,457,916 · genomes 0/152,286 · joint denominator

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.Cys255Phe
Coding: c.764G>T
MANE Select: NM_005619
dbSNP: rs775281770
Type: single nucleotide variant
Location: chr19:45494216 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 255: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic)

Full RTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

RTN2 p.Arg85Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Tyr495Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Val404Met Uncertain significance ★★ ⚠ same condition
RTN2 p.Ala381= Benign/Likely benign ★★ same condition
RTN2 p.Ala531= Benign/Likely benign ★★ same condition
RTN2 p.Gln117= Benign/Likely benign ★★ same condition
RTN2 p.Gly148= Benign/Likely benign ★★ same condition
RTN2 p.Gly390Ser Benign/Likely benign ★★ 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-cys255phe (accessed [today's date]).

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