Is RTN2 p.Ser540Pro (c.1618T>C) pathogenic?

RTN2 p.Ser540Pro (c.1618T>C) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-12-25). AlphaMissense: likely benign (0.1316); Ultra-rare (popmax 0.0183%, amr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ser540Pro (c.1618T>C)?

RTN2 p.Ser540Pro (c.1618T>C) is associated with Spastic paraplegia, hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Ser540Pro (c.1618T>C) in the general population?

RTN2 p.Ser540Pro (c.1618T>C) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about RTN2 p.Ser540Pro (c.1618T>C)?

AlphaMissense predicts likely benign (score 0.1316) — an in-silico prediction, not a clinical call.

RTN2 p.Ser540Pro

c.1618T>C · rs779865623 · VCV841510

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1316 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1316	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.37	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 3.9	GERP -0.067, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	20.4	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 0.0183% Admixed American · 11/59,988 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00328% 53/1,613,858 alleles · ultra-rare exomes 45/1,461,808 · genomes 8/152,050 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.00331%	30,256

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.Ser540Pro
Coding: c.1618T>C
MANE Select: NM_005619
dbSNP: rs779865623
Type: single nucleotide variant
Location: chr19:45485728 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 540: 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

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

Also linked: hereditary spastic paraplegia 12

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-ser540pro (accessed [today's date]).

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