Is RTN2 p.Pro315Thr (c.943C>A) pathogenic?

RTN2 p.Pro315Thr (c.943C>A) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-23). AlphaMissense: likely benign (0.0863); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 12.

What condition is associated with RTN2 p.Pro315Thr (c.943C>A)?

RTN2 p.Pro315Thr (c.943C>A) is associated with hereditary spastic paraplegia 12 (ClinVar).

How common is RTN2 p.Pro315Thr (c.943C>A) in the general population?

RTN2 p.Pro315Thr (c.943C>A) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal dominant spastic paraplegia type 12 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RTN2 p.Pro315Thr (c.943C>A)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

RTN2 p.Pro315Thr

c.943C>A · rs765944441 · VCV1028922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 12

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.99	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 8	GERP 1.8, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RTN2
Protein: p.Pro315Thr
Coding: c.943C>A
MANE Select: NM_005619
dbSNP: rs765944441
Type: single nucleotide variant
Location: chr19:45493250 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 315: 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 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 12 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

RTN2 p.Pro315Ser Uncertain significance ★★ ⚠ same residue
RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A Uncertain significance ★★ same condition
RTN2 p.Arg447Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Leu394Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser441Leu Uncertain significance ★★ ⚠ same condition
RTN2 p.Ser540Pro Uncertain significance ★★ ⚠ same condition
RTN2 p.Val471Met 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-pro315thr (accessed [today's date]).

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