Is RTN2 p.Ala536Val (c.1607C>T) pathogenic?

RTN2 p.Ala536Val (c.1607C>T) is classified Likely benign in RTN2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.1613); Rare (popmax 0.112%, afr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Ala536Val (c.1607C>T)?

RTN2 p.Ala536Val (c.1607C>T) is associated with Spastic paraplegia, hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Ala536Val (c.1607C>T) in the general population?

RTN2 p.Ala536Val (c.1607C>T) is rare (popmax 0.112%, afr) (gnomAD).

What do computational predictors say about RTN2 p.Ala536Val (c.1607C>T)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

RTN2 p.Ala536Val

c.1607C>T · rs140567426 · VCV893520

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -8.74	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 4.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	24.4	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 0.112% African / African-American · 84/75,044 alleles

Filtering AF 0.0926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00582% 94/1,614,116 alleles · rare exomes 59/1,461,812 · genomes 35/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	893
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00333%	30,010
European (non-Finnish)	0.000254%	393,335

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.Ala536Val
Coding: c.1607C>T
MANE Select: NM_005619
dbSNP: rs140567426
Type: single nucleotide variant
Location: chr19:45485739 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 536: 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-ala536val (accessed [today's date]).

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